Geochemical Fate and Transport of Sildenafil and Vardenafil

NASA Astrophysics Data System (ADS)

Richter, L.; Boudinot, G.; Vulava, V. M.; Cory, W. C.

2015-12-01

The geochemical fate of pharmaceuticals and their degradation products is a developing environmental field. The geologic, chemical, and biological fate of these pollutants has become very relevant with the increase in human population and the resulting increase in pollutant concentrations in the environment. In this study, we focus on sildenafil (SDF) and vardenafil (VDF), active compounds in Viagra and Levitra, respectively, two commonly used erectile dysfunction drugs. The main objective is to determine the sorption potential and transport behavior of these two compounds in natural soils. Both SDF and VDF are complex organic molecules with multiple amine functional groups in their structures. Two types of natural acidic soils (pH≈4.5), an organic-rich soil (7.6% OM) and clay-rich soil (5.1% clay) were used in this study to determine which soil components influence sorption behavior of both compounds. Sorption isotherms measured using batch reactors were nearly linear, but sorption was stronger in soil that contained higher clay content. Both compounds have multiple pKas due to the amine functional groups, the relevant pKas of SDF are 5.97 and 7.27, and those of VDF's are 4.72 and 6.21. These values indicate that these compounds likely behave as cations in soil suspensions and hence were strongly sorbed to negatively-charged clay minerals present in both soils. The clay composition in both soils is predominantly kaolinite with smaller amount of montmorillonite, both of which have a predominantly negative surface charge. Transport experiments using glass chromatography columns indicated that both compounds were more strongly retarded in the clay-rich soils. Breakthrough curves from the transport experiments were modeled using convection-dispersion transport equations. The organic matter in the soil seemed to play a less dominant role in the geochemistry in this study, but is likely to transform both compounds into derivative compounds as seen in other studies.

[Update of PDE5 inhibitors as treatment of ED].

PubMed

Lu, Yong-ning; Chen, Bin

2005-07-01

Erectile dysfunction is a common ailment in middle-aged and old men. The management of ED has entered a new stage since sildenafil was used to treat ED in 1998. Sildenafil became the first-line treatment for its efficacy and safety. In recent years, new PDE5 inhibitors--vardenafil and tadalafil came into market in succession, providing more options available for oral therapy. This review is about the development of preclinical and clinical medicine research on the three PDE5 inhibitors, and provide information for clinical choices.

The LC/MS Quantitation of Vardenafil (Levitra) in Postmortem Biological Specimens

DTIC Science & Technology

2006-01-01

inhibition. Int J Impot Res. 16 Suppl 1: S11-4 (2004). 10. TOXI-NEWS. Sildenafil ( viagra ). TOXI-LAB, Irvine, CA,. 18: 1 (1999). 11. Borrillo, D.J...Dangers of Viagra use in pilots. Federal Air Surg Med Bull. 98-3:1 (1998). 12. Bischoff, E. Vardenafil preclinical trial data: Po- tency

Sildenafil protects against 3-nitropropionic acid neurotoxicity through the modulation of calpain, CREB, and BDNF.

PubMed

Puerta, Elena; Hervias, Isabel; Barros-Miñones, Lucía; Jordan, Joaquin; Ricobaraza, Ana; Cuadrado-Tejedor, Mar; García-Osta, Ana; Aguirre, Norberto

2010-05-01

In this study we tested whether phosphodiesterase 5 (PDE5) inhibitors, sildenafil and vardenafil, would afford protection against 3-nitropropionic acid (3NP), which produces striatal lesions that closely mimic some of the neuropathological features of Huntington's Disease (HD). The neurotoxin was given over 5 days by constant systemic infusion using osmotic minipumps. Animals treated with PDE5 inhibitors (sildenafil or vardenafil) showed improved neurologic scores, reduced the loss of striatal DARPP-32 protein levels and lesion volumes, and decreased calpain activation produced by 3NP. This protective effect was independent of changes in 3NP-induced succinate dehydrogenase inhibition. Furthermore, striatal p-CREB levels along with the expression of BDNF were significantly increased in sildenafil-treated rats. In summary, PDE5 inhibitors protected against 3NP-induced striatal degeneration by reducing calpain activation and by promoting survival pathways. These data encourage further evaluation of PDE5 inhibitors in transgenic mouse models of HD. Copyright 2010 Elsevier Inc. All rights reserved.

Co-possession of phosphodiesterase type-5 inhibitors (PDE5-I) with nitrates.

PubMed

Chang, Li-Ling; Ma, Mark; Allmen, Heather von; Henderson, Scott C; Harper, Kristine; Hornbuckle, Kenneth

2010-06-01

Estimate the proportion of phosphodiesterase type-5 inhibitor (PDE5-I) patients who co-possess nitrates and compare the proportion of tadalafil patients dispensed nitrates to a matched control group. Secondarily, examine the percentage of co-possession of PDE5-Is and nitrates where the products were dispensed on the same day or written by the same prescriber. Male patients aged 18+ years filling PDE5-I prescriptions between December 2003 and March 2006 were identified using a U.S. longitudinal prescription database (IMS Health LRx). Similar patients not dispensed a PDE5-I during this period were matched to the tadalafil-dispensed cohort using a propensity score approach. Co-possession, as a proxy for concurrent use, was defined as an overlap in time on therapy for a PDE5-I and nitrate and was compared for the three PDE5-Is and for tadalafil to the matched control group. Among 601,063 tadalafil patients, 3.31% were dispensed a nitrate during the study period, compared to 6.18% in control patients (n = 601,063). When co-possessed prescriptions were defined by overlapping exposure periods, the proportion of PDE5-I patients with co-possessed nitrates ranged from 1.44% (tadalafil) to 1.72% (vardenafil) and 2.13% (sildenafil). Co-possession percentages of PDE5-I prescriptions were 0.83% for tadalafil and 1.07% for sildenafil and vardenafil. The majority (54.29%) of co-possessed PDE5-I and nitrate prescriptions had the nitrate dispensed prior to the PDE5-I prescription identified in the study cohort. Keeping in mind the limitations of observational studies, these results suggest that co-dispensing of nitrates and PDE5-Is is low. Compared to control patients, the proportion of nitrate co-possession was lowest for patients filling tadalafil. Tadalafil patients also had the lowest co-possessed proportion among the three PDE5-I cohorts. While the majority of co-possessed drug pairs were prescribed by different providers, the highest percentage of co-prescribing from the same

The application of quantitative methods for identifying and exploring the presence of bias in systematic reviews: PDE-5 inhibitors for erectile dysfunction.

PubMed

Bekkering, G E; Abou-Setta, A M; Kleijnen, J

2008-01-01

A systematic review of PDE-5 inhibitors for erectile dysfunction was performed to evaluate the utility of quantitative methods for identifying and exploring the influence of bias and study quality on pooled outcomes from meta-analyses. We included 123 randomized controlled trials (RCTs). Methodological quality was poorly reported. All three drugs appeared highly effective. Indirect adjusted analyses showed no differences between the three drugs. Funnel plots and statistical tests showed no evidence of small-study effects for sildenafil whereas there was evidence of such bias for tadalafil and vardenafil. Adjustment for missing studies using trim and fill techniques did not alter the pooled estimates substantially. The exclusion of previous sildenafil nonresponders was associated with larger treatment effects for tadalafil. This investigation was hampered by poor reporting of methodological quality, a low number of studies, heterogeneity and large effect sizes. Despite such limitations, a comprehensive assessment of biases should be a routine in systematic reviews.

Vardenafil orodispersible tablet.

PubMed

Sanford, Mark

2012-01-01

Vardenafil orodispersible tablet (ODT) is a supralingual formulation of vardenafil that is available for the on-demand treatment of erectile dysfunction. The pharmacokinetics of vardenafil ODT are not equivalent to those of the vardenafil film-coated tablet in that the ODT formulation provides consistently greater vardenafil systemic exposure. Therefore, the two formulations are not interchangeable. The efficacy of on-demand vardenafil ODT 10 mg was established in the POTENT I and II studies, which were 6-week, randomized, double-blind, multinational trials in men with erectile dysfunction of at least 6 months duration. In both trials, vardenafil ODT improved erectile function significantly more than placebo, as indicated by International Index of Erectile Function-Erectile Function subscale scores at week 12 and overall erection success rates during treatment according to responses to questions 2 and 3 of the Sexual Encounter Profile (coprimary endpoints). In a pooled analysis of both trials, vardenafil ODT improved erectile function regardless of age, severity of erectile dysfunction at baseline or the presence or absence of underlying medical conditions. Vardenafil ODT was generally well tolerated in clinical trials, including in men aged ≥65 years, and adverse events were mostly mild or moderate in severity.

A review of synthetic phosphodiesterase type 5 inhibitors (PDE-5i) found as adulterants in dietary supplements.

PubMed

Kee, Chee-Leong; Ge, Xiaowei; Gilard, Véronique; Malet-Martino, Myriam; Low, Min-Yong

2018-01-05

To date, there are 80 synthetic PDE-5i found as adulterants in dietary supplements. Analogues of sildenafil remain as the top list with 50 (62%) and are followed by analogues of tadalafil, 21 (26%), analogues of vardenafil, 7 (9%) and others, 2 (3%). The sildenafil group can be sub-categorized into sulphonamide-bonded (24, 48%), acetyl-bonded (11, 22%), carbonyl or thiocarbonyl-bonded (8, 16%) and other types (7, 14%) based on the functional group linked to pyrazolopyrimidine-one moieties. Meanwhile, analogues of tadalafil have become popularly found as adulterants in dietary supplements like beverages and herbal extracts from 2015 to 2016. The uptrend has been observed with the increase in number and complexity with more trans-oriented and dimerized tadalafil analogues being reported. Interestingly, there is no much increase for analogues of vardenafil. About two thirds of analogues have been reported from the Asian countries (67%), followed by Europe (22%) and North America (11%). South Korea and Singapore have reported the most number of analogues with a total number of 40 (50%). One plausible contributing factor to this trend is the convenient purchase of sexual enhancement dietary supplements, especially the on-line purchase. In terms of analytical methodologies, high performance liquid chromatography (HPLC) hyphenated to ultra-violet (UV) and/or mass spectrometry (MS) detection have been preferred in the screening analysis, i.e. 70 out of 77 compounds have been analysed by HPLC-UV. In addition, the electrospray ionization multistage fragmentation experiments (ESI-MS n ) for acquiring low- and high-resolution mass spectra have been successfully applied to detect and quantify PDE-5i in adulterated products simultaneously. Nuclear magnetic resonance (NMR) is another important technique in the structural elucidation of novel analogues. Copyright © 2017 Elsevier B.V. All rights reserved.

Sexual life of Japanese patients with erectile dysfunction taking phosphodiesterase type 5 inhibitors: an Internet survey using the Psychological and Interpersonal Relationship Scales-Short Form questionnaire.

PubMed

Tsujimura, Akira; Kiuchi, Hiroshi; Soda, Tetsuji; Takezawa, Kentaro; Okuda, Hidenobu; Fukuhara, Shinichiro; Takao, Tetsuya; Nonomura, Norio; Miyagawa, Yasushi

2014-08-01

To investigate details of sexual function of erectile dysfunction in Japanese patients taking phosphodiesterase type 5 inhibitors. A Japanese version of the Psychological and Interpersonal Relationship Scales-Short Form was used to carry out a nationwide survey using the Internet. A total of 556 erectile dysfunction patients (age 30-70 years) who had been prescribed a phosphodiesterase type 5 inhibitor and had attempted sexual intercourse within the past 6 months were included in this survey. Scores were compared in relation to the phosphodiesterase type 5 inhibitors most frequently taken within the past 6 months. In the subdomains of self-confidence and spontaneity of the Psychological and Interpersonal Relationship Scales-Short Form, scores for vardenafil and tadalafil were significantly higher than those for sildenafil. In the subdomain of time concern of the Psychological and Interpersonal Relationship Scales-Short Form, the score for tadalafil was significantly lower than that for others. Our findings support the hypothesis that Japanese patients with erectile dysfunction have high sexual self-confidence, spontaneity and low time concerns when taking tadalafil. These characteristics of tadalafil could be associated with high patient satisfaction and high preference. © 2014 The Japanese Urological Association.

[Phosphodiesterase-5 inhibitors for the treatment of pulmonary arterial hypertension].

PubMed

Beltrán-Gámez, Miguel E; Sandoval-Zárate, Julio; Pulido, Tomás

2015-01-01

In experimental and clinical cardiology, phosphodiesterase type 5 (PDE-5) inhibitors have brought scientific interest as a therapeutic tool in pulmonary arterial hypertension (PAH) management in recent years. Phosphodiesterases are a superfamily of enzymes that inactivate cyclic adenosine monophosphate and cyclic guanosine monophosphate, the second messengers of prostacyclin and nitric oxide. The rationale for the use of PDE-5 inhibitors in PAH is based on their capacity to overexpresss the nitric oxide pathway pursued inhibition of cyclic guanosine monophosphate hydrolysis. By increasing cyclic guanosine monophosphate levels it promotes vasodilation, antiproliferative and pro-apoptotic effects that may reverse pulmonary vascular remodeling. There is also evidence that these drugs may directly enhance right ventricular contractility through an increase in cyclic adenosine monophosphate mediated by the inhibition of the cyclic guanosine monophosphate -sensitive PDE-3. Sildenafil, tadalafil and vardenafil are 3 specific PDE-5 inhibitors in current clinical use, which share similar mechanisms of action but present some significant differences regarding potency, selectivity for PDE-5 and pharmacokinetic properties. Sildenafil received approval in 2005 by the Food and Drug Administration and the European Medicines Agency and tadalafil in 2009 by the Food and Drug Administration and the European Medicines Agency for the treatment of PAH in patients classified as NYHA/WHO functional class II and III. In Mexico, sildenafil and tadalafil were approved by Comisión Federal de Protección contra Riesgos Sanitarios for this indication in 2010 and 2011, respectively. Copyright © 2014 Instituto Nacional de Cardiología Ignacio Chávez. Published by Masson Doyma México S.A. All rights reserved.

PDE5 inhibitor treatment persistence and adherence in Brazilian men: post-hoc analyses from a 6-month, prospective, observational study.

PubMed

Cairoli, Carlos; Reyes, Luis Antonio; Henneges, Carsten; Sorsaburu, Sebastian

2014-01-01

Characterize persistence and adherence to phosphodiesterase type - 5 inhibitor (PDE5I) on-demand therapy over 6 months among Brazilian men in an observational, non-interventional study of Latin American men naïve to PDE5Is with erectile dysfunction (ED). Men were prescribed PDE5Is per routine clinical practice. Persistence was defined as using ≥ 1 dose during the previous 4 - weeks, and adherence as following dosing instructions for the most recent dose, assessed using the Persistence and Adherence Questionnaire. Other measures included the Self - Esteem and Relationship (SEAR) Questionnaire, and International Index of Erectile Function (IIEF). Multivariate logistic regression was used to identify factors associated with persistence/adherence. 104 Brazilian men were enrolled; mean age by treatment was 53 to 59 years, and most presented with moderate ED (61.7%). The prescribed PDE5I was sildenafil citrate for 50 (48.1%), tadalafil for 36 (34.6%), vardenafil for 15 (14.4%), and lodenafil for 3 patients (2.9%). Overall treatment persistence was 69.2% and adherence was 70.2%; both were numerically higher with tadalafil (75.0%) versus sildenafil or vardenafil (range 60.0% to 68.0%). Potential associations of persistence and/or adherence were observed with education level, ED etiology, employment status, and coronary artery disease. Improvements in all IIEF domain scores, and both SEAR domain scores were observed for all treatments. Study limitations included the observational design, brief duration, dependence on patient self - reporting, and limited sample size. Approximately two-thirds of PDE5I-naive, Brazilian men with ED were treatment persistent and adherent after 6 months. Further study is warranted to improve long-term outcomes of ED treatment.

A 6 month, prospective, observational study of PDE5 inhibitor treatment persistence and adherence in Latin American men with erectile dysfunction.

PubMed

Rubio-Aurioles, Eusebio; Reyes, Luis Antonio; Borregales, Leonardo; Cairoli, Carlos; Sorsaburu, Sebastian

2013-06-01

To assess persistence/adherence rates of phosphodiesterase type-5 inhibitor (PDE5I) on-demand dosing in Latin American men with erectile dysfunction (ED), and explore patient characteristics and treatment factors that may be predictive for PDE5I persistence and adherence. Men from Brazil, Mexico, and Venezuela with ED who were naïve to PDE5Is were prescribed sildenafil, tadalafil, vardenafil, or lodenafil on-demand dosing and asked to provide information about PDE5I use at baseline and at 1, 3, and 6 months. Patients were persistent if they used ≥1 dose during the 4 week period prior to each evaluation. Patients were adherent if they complied with dosing instructions during most recent dose. Main outcome measures included Persistence and Adherence Questionnaire (PAQ), Partner Relationship Questionnaire (PRQ), Self-Esteem and Relationship (SEAR) Questionnaire, and International Index of Erectile Function (IIEF). Multivariate logistic regression was used to identify factors associated with persistence and adherence. A total of 511 men were enrolled; most had mild to moderate ED (77.1%); 317 patients (62.0%) were prescribed tadalafil, 116 (22.7%) sildenafil, 75 (14.7%) vardenafil, and 3 (0.6%) lodenafil (not further analyzed). A total of 340 patients (66.5%) were 'persistent' at 6 months; 345 (67.5%) were 'adherent'. Persistence and adherence were associated with age, education level, and ED duration. Reasons for non-persistence included medication cost and lack of efficacy. Study limitations included its design, brief observation period, its bias observed toward tadalafil selection; its dependence on patient self-reporting, limited number of factors that were analyzed for persistence/adherence association, its small number of participating patients and Latin American countries, and inherent differences in PDE5I preference and medical practices. Approximately two-thirds of PDE5I-naïve, Latin American men with ED were persistent and adherent after 6 months of

The management of erectile dysfunction: innovations and future perspectives.

PubMed

Leonardi, Rosario; Alemanni, Matteo

2011-03-01

Phosphodiesterase 5 (PDE5) inhibitors are recommended as first line therapy for the treatment of erectile dysfunction (ED). To date, three PDE5 inhibitors are on the market: sildenafil, vardenafil and tadalafil. These compounds are available as oral tablets; they are rapidly absorbed in the gastrointestinal tract and are excreted mainly in the fces and to a lexer extent in the urine. Recently, an orodisnersible formulation of feces and, to a lesser extent, in the urine. Recently, an orodispersible formulation of vardenafil (vardenafil ODT) has been developed, which is able to dissolve in the mouth within seconds, releasing a minty flavor, without the need of being swallowed with water. The clinical studies so far performed showed that vardenafil ODT has a bioavailability superior to the traditional film-coated tablet. Among the other PDE5 inhibitors under development we report mirodenafil, lodenafil carbonate, avalafil and SLx-2101 It is likely that in the future molecules that act on pathways other than the one of NO/cGMP will be available. Such as Rho-kinase inhibitors, which inhibit the mechanism that leads to smooth muscle contraction thus allowing erection and hydrogen sulphide (H2S), an endogenous molecule synthesized from cysteine that can be both a vasodilator and a vasoconstrictor according to its concentration.

Vardenafil

MedlinePlus

... not working well or if you are experiencing side effects.Vardenafil rapidly disintegrating tablets cannot be substituted for ... tablets are sweetened with aspartame, a source of phenylalanine.if you have fructose intolerance (an inherited condition ...

Simultaneous Detection of Three Phosphodiesterase Type 5 Inhibitors and Eight of Their Analogs in Lifestyle Products and Screening for Adulterants by High-Performance Thin-Layer Chromatography.

PubMed

Do, Tiên T K; Theocharis, Grigorios; Reich, Eike

2015-01-01

An HPTLC method is proposed to permit effective screening for the presence of three phosphodiesterase type 5 inhibitors (PDE5-Is; sildenafil, vardenafil, and tadalafil) and eight of their analogs (hydroxyacetildenafil, homosildenafil, thiohomosildenafil, acetildenafil, acetaminotadalafil, propoxyphenyl hydroxyhomosildenafil, hydroxyhomosildenafil, and hydroxythiohomosildenafil) in finished products, including tablets, capsules, chocolate, instant coffee, syrup, and chewing gum. For all the finished products, the same simple sample preparation may be applied: ultrasound-assisted extraction in 10 mL methanol for 30 min followed by centrifugation. The Rf values of individual HPTLC bands afford preliminary identification of potential PDE5-Is. Scanning densitometry capabilities enable comparison of the unknown UV spectra with those of known standard compounds and allow further structural insight. Mass spectrometric analysis of the material derived from individual zones supplies an additional degree of confidence. Significantly, the proposed screening technique allows focus on the already known PDE5 Is and provides a platform for isolation and chemical categorization of the newly-synthesized analogs. Furthermore, the scope could be expanded to other therapeutic categories (e.g., analgesics, antidiabetics, and anorexiants) that are occasionally coadulterated along with the PDE5-Is. The method was successfully applied to screening of 45 commercial lifestyle products. Of those, 31 products tested positive for at least one illegal component (sildenafil, tadalafil, propoxyphenyl hydroxyhomosildenafil, or dimethylsildenafil).

Efficacy and treatment satisfaction with on-demand tadalafil (Cialis) in men with erectile dysfunction.

PubMed

Skoumal, René; Chen, Juza; Kula, Krzysztof; Breza, Jan; Calomfirescu, Nicolae; Basson, Bruce R; Kopernicky, Vladimir

2004-09-01

Tadalafil (Cialis) is an inhibitor of phosphodiesterase type 5, which mediates relaxation of vascular smooth muscle in the corpus cavernosum thus facilitating erection. The purpose of this multicentre, randomized, double-blind, parallel group, placebo-controlled study was to evaluate efficacy and treatment satisfaction of on-demand Cialis in men with mild-to-severe erectile dysfunction (ED). Following a 4-week treatment-free run in period, patients stratified into three severity groups by the International Index of Erectile Function (IIEF) Erectile Function (EF) domain score were randomized to receive either placebo or Cialis 20 mg taken on demand over a 12-week period. Efficacy endpoints were change from baseline in IIEF EF domain scores, responses to Sexual Encounter Profile diary (SEP) questions, and responses to the Global Assessment Questions (GAQ). Treatment satisfaction was evaluated using the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questionnaire in two of seven participating countries where validated translations were available. Of the 443 men who entered the trial, 409 (mean age, 52 years) formed the intent-to-treat population. Mean baseline demographics and ED severity measures were balanced between treatment groups except for a higher percentage of patients naïve to sildenafil in the tadalafil group compared to placebo (50% versus 36%). The percentage of patients in each IIEF EF severity class (mild, moderate and severe) was 47%, 30% and 23% for placebo patients and 48%, 29% and 23% for tadalafil patients, respectively. Tadalafil was significantly superior to placebo on all primary efficacy measures (IIEF EF domain scores, SEP15, GAQ1; p < 0.001); notably 64% of tadalafil patients achieved a normal IIEF EF domain score at endpoint compared to 16% of placebo patients (p < 0.001). Of the 185 patients completing the EDITS questionnaire (137 receiving Cialis and 48 receiving placebo), tadalafil-treated patients had a median EDITS

PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer.

PubMed

Das, Anindita; Durrant, David; Salloum, Fadi N; Xi, Lei; Kukreja, Rakesh C

2015-03-01

The phosphodiesterase 5 (PDE5) inhibitors, including sildenafil (Viagra™), vardenafil (Levitra™), and tadalafil (Cialis™) have been developed for treatment of erectile dysfunction. Moreover, sildenafil and tadalafil are used for the management of pulmonary arterial hypertension in patients. Since our first report showing the cardioprotective effect of sildenafil in 2002, there has been tremendous growth of preclinical and clinical studies on the use of PDE5 inhibitors for cardiovascular diseases and cancer. Numerous animal studies have demonstrated that PDE5 inhibitors have powerful protective effect against myocardial ischemia/reperfusion (I/R) injury, doxorubicin cardiotoxicity, ischemic and diabetic cardiomyopathy, cardiac hypertrophy, Duchenne muscular dystrophy and the improvement of stem cell efficacy for myocardial repair. Mechanistically, PDE5 inhibitors protect the heart against I/R injury through increased expression of nitric oxide synthases, activation of protein kinase G (PKG), PKG-dependent hydrogen sulfide generation, and phosphorylation of glycogen synthase kinase-3β - a master switch immediately proximal to mitochondrial permeability transition pore and the end effector of cardioprotection. In addition, PDE5 inhibitors enhance the sensitivity of certain types of cancer to standard chemotherapeutic drugs, including doxorubicin. Many clinical trials with PDE5 inhibitors have focused on the potential cardiovascular and anti-cancer benefits. Despite mixed results of these clinical trials, there is a continuing strong interest by basic scientists and clinical investigators in exploring their new clinical uses. It is our hope that future new mechanistic investigations and carefully designed clinical trials would help in reaping additional benefits of PDE5 inhibitors for cardiovascular disease and cancer in patients. Copyright © 2014 Elsevier Inc. All rights reserved.

[Are there counterfeit medicines in Croatia?].

PubMed

Tomić, Sinisa; Milcić, Neven; Sokolić, Milenko; Sucić, Anita Filipović; Martinac, Adrijana Ilić

2010-01-01

Counterfeit medicines are a growing problem in the world, for their use may endanger patient's health and therefore they pose an enormous public health risk. The manufacture of counterfeit medicines usually involves organised crime groups which place the counterfeit medicines on the market for reasons of profit. Detection and prevention of trade in counterfeit medicines requires close cooperation between medicine regulatory authorities, police, customs, judiciary and pharmaceutical industry. To this day, there have been no recorded cases of counterfeit medicines in the legal supply chain in Croatia. However, medicines without marketing authorisation in Croatia, originating from different countries, could be found on the illegal market. Most frequently, this includes medicines for the treatment of erectile dysfunction such as: sildenafil, tadalafil, vardenafil. In this study, 26 medicines for the treatment of erectile dysfunction, seized in illegal supply chain, were tested. High performance liquid chromatography (HPLC) was used for identification and quantification of active substances in the tested samples. It was determined that 13 out of 26 samples did not comply with declared composition of medicine and quality specification. Furthermore, two samples did not contain declared active substance vardenafil and that may indicate that these medicines are counterfeit.

Use of combined intracorporal injection and a phosphodiesterase-5 inhibitor therapy for men with a suboptimal response to sildenafil and/or vardenafil monotherapy after radical retropubic prostatectomy.

PubMed

Mydlo, Jack H; Viterbo, Rosalia; Crispen, Paul

2005-04-01

To report experience with combined therapy using intracorporal injection (ICI) of alprostadil and oral phosphodiesterase 5 (PDE-5) inhibitors for the minimally invasive treatment of erectile dysfunction (ED) after radical prostatectomy (RP), as PDE-5 inhibitors are effective but a few patients may have a suboptimal response. In a retrospective study, 34 men (aged 46-66 years) had a nerve-sparing retropubic RP and subsequent ED. Patients were titrated on sildenafil citrate or vardenafil to maximum doses. All had a suboptimal response after a maximum of eight doses of oral therapy and were then treated with ICI therapy using 15 or 20 microg alprostadil. Erectile function was assessed with the Sexual Health Inventory for Men (SHIM). Of the 32 patients who continued combined therapy, 22 (68%) had an improvement in erectile function after ICI therapy, as assessed by the SHIM score. On follow-up, 36% of these patients used ICI therapy only intermittently, instead of regularly, as they felt that this was adequate enough for good results. PDE-5 oral pharmacotherapy is the most commonly used effective therapy for ED but may not be as effective in patients who have radical surgery; the addition of testosterone patches may have side-effects or be considered a risk in patients with a history of prostate cancer. The use of ICI therapy as an adjunct or maintenance therapy to their oral medication may be another alternative in these patients.

Pharmacotherapy of Sexual Dysfunctions : Current Status

PubMed Central

Avasthi, Ajith; Biswas, Parthasarathy

2004-01-01

The sexual dysfunctions are one of the most prevalent conditions. Sexual dysfunctions can have profound effect on the psychological well-being of an individual and the psychosexual relationship of a couple. Management of the sexual dysfunction should be preceded by an accurate diagnosis reached after a complete medical and sexual history and physical examination. Current focus of researchers has been on understanding the pathophysiology of erectile dysfunction, premature ejaculation and other sexual dysfunctions that can help in developing newer pharmacological cures for these conditions. Recently, a number of clinical trials have studied the potential effectiveness of the phosphodiesterase (PDE)-5 inhibitor sildenafil in the treatment of Erectile Dysfunction (ED) and Premature Ejaculation (PME). The introduction of PDE-5 inhibitors like sildenafil, vardenafil and tadalafil has revolutionized the treatment of sexual dysfunctions. This review focuses on the recent pharmacological advances in the treatment of common sexual dysfunctions like ED and PME with special focus on the role of PDE-5 inhibitors. Also discussed is the pharmacological treatment of other less prevalent and recognized disorders like female sexual dysfunction, drug induced sexual dysfunction etc. PMID:21224902

Tadalafil-loaded nanostructured lipid carriers using permeation enhancers.

PubMed

Baek, Jong-Suep; Pham, Cuong Viet; Myung, Chang-Seon; Cho, Cheong-Weon

2015-11-30

Tadalafil is a phosphodiesterase-5 inhibitor indicated for the treatment of erectile dysfunction. In this study, we prepared and evaluated transdermal nanostructured lipid carriers (NLC) to improve the skin permeability of tadalafil. Tadalafil-loaded NLC dispersions were prepared using glyceryl monostearate as a solid lipid, oleic acid as a liquid lipid, and Tween 80 as a surfactant. We characterized the dispersions according to particle size, polydispersity index, zeta potential, encapsulation efficiency, and transmission electron microscopy. In vitro skin permeation studies were carried out using Franz diffusion cells, and cytotoxicity was examined using HaCaT keratinocyte cell lines. Tadalafil skin permeability increased for all tadalafil-loaded NLC formulations. The tadalafil-loaded NLC dispersion with ethanol and limonene as skin permeation enhancers exhibited the highest flux (∼4.8-fold) compared to that observed with tadalafil solution alone. Furthermore, a tadalafil-loaded NLC gel with selected permeation enhancers showed tolerance against toxicity in HaCaT cells. These results suggest that the NLC formulations with ethanol and limonene as skin permeation enhancers could be a promising dermal delivery carrier for tadalafil. Copyright © 2015 Elsevier B.V. All rights reserved.

In silico design of novel hERG-neutral sildenafil-like PDE5 inhibitors.

PubMed

Kayık, Gülru; Tüzün, Nurcan Ş; Durdagi, Serdar

2017-10-01

Cyclic nucleotide phosphodiesterase enzymes (PDEs) have functions in regulating the levels of intracellular second messengers, 3', 5'-cyclic adenosine monophosphate (cAMP) and 3', 5'-cyclic guanosine monophosphate (cGMP), via hydrolysis and decomposing mechanisms in cells. They take essential roles in modulating various cellular activities such as memory and smooth muscle functions. PDE type 5 (PDE5) inhibitors enhance the vasodilatory effects of cGMP in the corpus cavernosum and they are used to treat erectile dysfunction. Patch clamp experiments showed that the IC 50 values of the human ether-à-go-go-related gene (hERG1) potassium (K) ion channel blocking affinity of PDE5 inhibitors sildenafil, vardenafil, and tadalafil as 33, 12, and 100 μM, respectively. hERG1 channel is responsible for the regulation of the action potential of human ventricular myocyte by contributing the rapid component of delayed rectifier K + current (I Kr ) component of the cardiac action potential. In this work, interaction patterns and binding affinity predictions of selected PDE5 inhibitors against the hERG1 channel are studied. It is attempted to develop PDE5 inhibitor analogs with lower binding affinity to hERG1 ion channel while keeping their pharmacological activity against their principal target PDE5 using in silico methods. Based on detailed analyses of docking poses and predicted interaction energies, novel analogs of PDE5 inhibitors with lower predicted binding affinity to hERG1 channels without loosing their principal target activity were proposed. Moreover, molecular dynamics (MD) simulations and post-processing MD analyses (i.e. Molecular Mechanics/Generalized Born Surface Area calculations) were performed. Detailed analysis of molecular simulations helped us to better understand the PDE5 inhibitor-target binding interactions in the atomic level. Results of this study can be useful for designing of novel and safe PDE5 inhibitors with enhanced activity and other tailored

Tadalafil

MedlinePlus

... Tadalafil is also sometimes taken once a day every day without regard to timing of sexual activity. You ... schedule, take it at around the same time every day. If you have certain health conditions or are ...

Efficacy and safety of vardenafil in men with erectile dysfunction caused by spinal cord injury.

PubMed

Giuliano, F; Rubio-Aurioles, E; Kennelly, M; Montorsi, F; Kim, E D; Finkbeiner, A E; Pommerville, P J; Colopy, M W; Wilkins, H J; Wachs, B H

2006-01-24

To assess the efficacy and tolerability of vardenafil in men with erectile dysfunction (ED) due to traumatic spinal cord injury (SCI). In this multicenter, double-blind, placebo-controlled, parallel-group 12-week study, 418 men aged 18 years and older with ED for more than 6 months consequent to SCI were randomized to vardenafil (n = 207) or placebo (n = 211) (10 mg for 4 weeks, then maintained or titrated to 5 or 20 mg at weeks 4 and 8). Efficacy assessments included the erectile function (EF) domain score of the International Index of Erectile Function questionnaire and diary questions regarding penetration, maintenance of erection to completion of intercourse, and ejaculation. Baseline patient characteristics were similar in the vardenafil (mean age 40 years) and placebo (mean age 39 years) groups. Mean baseline EF domain scores were 11.6 in the vardenafil group and 12.1 (moderate ED) in the placebo group. EF domain score in the vardenafil group improved to 22.0 (mild ED) at last observation carried forward vs 13.5 in the placebo group (p < 0.001). Over 12 weeks of treatment, mean per-patient penetration (76% vs 41%), maintenance (59% vs 22%), and ejaculation (19% vs 10%) success rates were significantly greater vs placebo (all p < 0.001). The most frequently reported drug-related adverse events were headache (vardenafil 15%, placebo 4%), flushing (vardenafil 6%, placebo 0%), nasal congestion (vardenafil 5%, placebo 0%), and dyspepsia (vardenafil 4%, placebo 0%). Vardenafil significantly improved erectile and ejaculatory function and was generally well tolerated in men with erectile dysfunction due to spinal cord injury.

Phosphodiesterase type 5 inhibitor abuse: a critical review.

PubMed

Lowe, Gregory; Costabile, Raymond

2011-06-01

Abuse of sildenafil has been reported since its introduction in 1999 and commonly documented in combination with illicit drugs among men and women of all ages. Increased risks of sexually transmissible diseases including HIV have been associated with sildenafil use in men who have sex with men. Recognizing the abuse potential of phosphodiesterase type 5 inhibitors (PDE5), we aim to summarize the current knowledge of this abuse. An investigation of EMBASE, PubMed, the Food and Drug Administration (FDA) website, MedWatch, and search engines was performed to evaluate information regarding sildenafil, tadalafil, and vardenafil abuse. The EMBASE search provided 46 articles fitting the search criteria and evaluation led to 21 separate publications with specific information regarding PDE5 abuse. A PubMed search found 10 additional publications. MedWatch reported 44 separate warnings since 2000, most of which reported contamination of herbal products with active drug components. Few reports of abuse were among the 14,818 reports in the FDA AERS for sildenafil. A search for "internet drug store" revealed 6.4 million hits and of 7000 internet pharmacies identified by the Verified Internet Pharmacy Practice Sites Program (VIPPS) only 4% were in proper compliance. The role internet pharmacies play in counterfeit PDE5 or abuse is not well documented; however based on easy access, direct patient marketing, and low advertised cost it is likely this role is underreported. Currently the best recommendation for providers is to recognize the possibility of abuse and to educate patients on risks of this behavior.

Discovery of novel pyrazolopyrimidinone analogs as potent inhibitors of phosphodiesterase type-5.

PubMed

Sawant, Sanghapal D; Lakshma Reddy, G; Dar, Mohd Ishaq; Srinivas, M; Gupta, Gourav; Sahu, Promod Kumar; Mahajan, Priya; Nargotra, Amit; Singh, Surjeet; Sharma, Subhash C; Tikoo, Manoj; Singh, Gurdarshan; Vishwakarma, Ram A; Syed, Sajad Hussain

2015-05-01

Cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type-5 (PDE5), a clinically proven target to treat erectile dysfunction and diseases associated with lower cGMP levels in humans, is present in corpus cavernosum, heart, lung, platelets, prostate, urethra, bladder, liver, brain, and stomach. Sildenafil, vardenafil, tadalafil and avanafil are FDA approved drugs in market as PDE5 inhibitors for treating erectile dysfunction. In the present study a lead molecule 4-ethoxy-N-(6-hydroxyhexyl)-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonamide, that is, compound-4a, an analog of pyrazolopyrimidinone scaffold has been identified as selective PDE5 inhibitor. A series of compounds was synthesized by replacing N-methylpiperazine moiety (ring-C) of sildenafil structure with different N-substitutions towards sulfonamide end. Compound-4a showed lower IC₅₀ value (1.5 nM) against PDE5 than parent sildenafil (5.6 nM) in in vitro enzyme assay. The isoform selectivity of the compound-4a against other PDE isoforms was similar to that of the Sildenafil. In corroboration with the in vitro data, this molecule showed better efficacy in in vivo studies using the conscious rabbit model. Also compound-4a exhibited good physicochemical properties like solubility, caco-2 permeability, cLogP along with optimal PK profile having no significant CYP enzyme inhibitory liabilities. Discovery of these novel bioactive compounds may open a new alternative for developing novel preclinical candidates based on this drugable scaffold. Copyright © 2015 Elsevier Ltd. All rights reserved.

Efficacy of Continuous Dosing of Tadalafil Once Daily vs Tadalafil On Demand in Clinical Subgroups of Men With Erectile Dysfunction: A Descriptive Comparison Using the Integrated Tadalafil Databases.

PubMed

Brock, Gerald; Ni, Xiao; Oelke, Matthias; Mulhall, John; Rosenberg, Matt; Seftel, Allen; D'Souza, Deborah; Barry, Jane

2016-05-01

Various factors play a role in the development of erectile dysfunction (ED). To provide a descriptive comparison of erectile function response for tadalafil on-demand (PRN) and once-daily (OAD) dosing regimens in patients with common comorbid conditions, treatments, or risk factors that can be considered when treating ED. In total, 17 PRN and 4 OAD placebo-controlled studies were included in the integrated database in these pooled analyses. Data were analyzed from patients treated with placebo, tadalafil 10 mg (low dose), and 20 mg (high dose) for the PRN studies and placebo, tadalafil 2.5 mg (low dose), and 5 mg (high dose) for the OAD studies. The effects of tadalafil were measured using the International Index of Erectile Function administered from baseline to week 12. A descriptive comparison of the efficacy of tadalafil PRN vs OAD was examined in the clinical populations. Baseline characteristics of 4,354 men were comparable between the PRN and OAD groups, with differences seen only in the variables of race, body mass index (BMI) of at least 30 kg/m(2), and alcohol use. Tadalafil was efficacious at improving erectile function for all clinical populations, except for the low-dose OAD group, which demonstrated a weaker effect vs placebo than the high-dose OAD group, and the low- and high-dose PRN groups vs placebo for patients with BMI of at least 30 kg/m(2) for patients without a cardiovascular disorder, smokers, patients with ED duration shorter than 1 year, and patients without previous phosphodiesterase type 5 inhibitor use. Tadalafil was efficacious for patients with or without diabetes mellitus, arterial hypertension, hyperlipidemia, and alcohol use at baseline. Tadalafil OAD and PRN regimens showed efficacy in patients with ED. No clinical populations of patients with ED seemed to benefit overwhelmingly from one dose regimen over the other. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Acute Intracranial and Spinal Subdural Hematoma Associated with Vardenafil.

PubMed

Nakamura, Takaaki; Watanabe, Genya; Harada, Ryuhei; Kawasaki, Emiko; Tsukita, Kenichi; Suzuki, Yasushi

2018-05-02

A 28-year-old healthy man was admitted to our hospital because of right-sided headache, vomiting, and lower back pain after the administration of vardenafil. Computed tomography and magnetic resonance imaging of the brain showed a small, right-sided, subdural hematoma. A lumbar magnetic resonance imaging showed a longitudinally extended subdural hematoma. He had no history of trauma. We speculated that vardenafil might have had an association with the bleeding. Several reports have suggested a relationship between phosphodiesterase-5 inhibitors and intracerebral or subarachnoid hemorrhage. Our case suggested that there may also be risks of bleeding into the subdural space. Although headache and nausea are common side effects of vardenafil, hemorrhagic diseases should also be considered when symptoms are severe or prolonged. Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.

PDE5 inhibitors blunt inflammation in human BPH: a potential mechanism of action for PDE5 inhibitors in LUTS.

PubMed

Vignozzi, Linda; Gacci, Mauro; Cellai, Ilaria; Morelli, Annamaria; Maneschi, Elena; Comeglio, Paolo; Santi, Raffaella; Filippi, Sandra; Sebastianelli, Arcangelo; Nesi, Gabriella; Serni, Sergio; Carini, Marco; Maggi, Mario

2013-09-01

Metabolic syndrome (MetS) and benign prostate hyperplasia (BPH)/low urinary tract symptoms (LUTS) are often comorbid. Chronic inflammation is one of the putative links between these diseases. Phosphodiesterase type 5 inhibitors (PDE5i) are recognized as an effective treatment of BPH-related LUTS. One proposed mechanism of action of PDE5 is the inhibition of intraprostatic inflammation. In this study we investigate whether PDE5i could blunt inflammation in the human prostate. Evaluation of the effect of tadalafil and vardenafil on secretion of interleukin 8 (IL-8, a surrogate marker of prostate inflammation) by human myofibroblast prostatic cells (hBPH) exposed to different inflammatory stimuli. We preliminary evaluate histological features of prostatic inflammatory infiltrates in BPH patients enrolled in a randomized, double bind, placebo controlled study aimed at investigating the efficacy of vardenafil (10 mg/day, for 12 weeks) on BPH/LUTS. In vitro treatment with tadalafil or vardenafil on hBPH reduced IL-8 secretion induced by either TNFα or metabolic factors, including oxidized low-density lipoprotein, oxLDL, to the same extent as a PDE5-insensitive PKG agonist Sp-8-Br-PET-cGMP. These effects were reverted by the PKG inhibitor KT5823, suggesting a cGMP/PKG-dependency. Treatment with tadalafil or vardenafil significantly suppressed oxLDL receptor (LOX-1) expression. Histological evaluation of anti-CD45 staining (CD45 score) in prostatectomy specimens of BPH patients showed a positive association with MetS severity. Reduced HDL-cholesterol and elevated triglycerides were the only MetS factors significantly associated with CD45 score. In the MetS cohort there was a significant lower CD45 score in the vardenafil-arm versus the placebo-one. © 2013 Wiley Periodicals, Inc.

Phosphodiesterase Type 5 Inhibitors, Sport and Doping.

PubMed

Di Luigi, Luigi; Sansone, Massimiliano; Sansone, Andrea; Ceci, Roberta; Duranti, Guglielmo; Borrione, Paolo; Crescioli, Clara; Sgrò, Paolo; Sabatini, Stefania

Phosphodiesterase type 5 inhibitors (PDE5i) (e.g., sildenafil, tadalafil, vardenafil, and avanafil) are drugs commonly used to treat erectile dysfunction, pulmonary arterial hypertension, and benign prostatic hyperplasia. PDE5i are not prohibited by the World Anti-Doping Agency (WADA) but are alleged to be frequently misused by healthy athletes to improve sporting performance. In vitro and in vivo studies have reported various effects of PDE5i on cardiovascular, muscular, metabolic, and neuroendocrine systems and the potential, therefore, to enhance performance of healthy athletes during training and competition. This suggests well-controlled research studies to examine the ergogenic effects of PDE5i on performance during activities that simulate real sporting situations are warranted to determine if PDE5i should be included on the prohibited WADA list. In the meantime, there is concern that some otherwise healthy athletes will continue to misuse PDE5i to gain an unfair competitive advantage over their competitors.

Results of vardenafil mediated power Doppler ultrasound, contrast enhanced ultrasound and systematic random biopsies to detect prostate cancer.

PubMed

Morelli, Girolamo; Pagni, Riccardo; Mariani, Chiara; Minervini, Riccardo; Morelli, Andrea; Gori, Francesco; Ferdeghini, Ezio Maria; Paterni, Marco; Mauro, Eva; Guidi, Elisa; Armillotta, Nicola; Canale, Domenico; Vitti, Paolo; Caramella, Davide; Minervini, Andrea

2011-06-01

We evaluated the ability of the phosphodiesterase-5 inhibitor vardenafil to increase prostate microcirculation during power Doppler ultrasound. We also evaluated the results of contrast and vardenafil enhanced targeted biopsies compared to those of standard 12-core random biopsies to detect cancer. Between May 2008 and January 2010, 150 consecutive patients with prostate specific antigen more than 4 ng/ml at first diagnosis with negative digital rectal examination and transrectal ultrasound, and no clinical history of prostatitis underwent contrast enhanced power Doppler ultrasound (bolus injection of 2.4 ml SonoVue® contrast agent), followed by vardenafil enhanced power Doppler ultrasound (1 hour after oral administration of vardenafil 20 mg). All patients underwent standard 12-core transrectal ultrasound guided random prostate biopsy plus 1 further sampling from each suspected hypervascular lesion detected by contrast and vardenafil enhanced power Doppler ultrasound. Prostate cancer was detected in 44 patients (29.3%). Contrast and vardenafil enhanced power Doppler ultrasound detected suspicious, contrast enhanced and vardenafil enhanced areas in 112 (74.6%) and 110 patients (73.3%), and was diagnostic for cancer in 32 (28.5%) and 42 (38%), respectively. Analysis of standard technique, and contrast and vardenafil enhanced power Doppler ultrasound findings by biopsy core showed significantly higher detection using vardenafil vs contrast enhanced power Doppler ultrasound and standard technique (41.2% vs 22.7% and 8.1%, p <0.005 and <0.001, respectively). The detection rate of standard plus contrast or vardenafil enhanced power Doppler ultrasound was 10% and 11.7% (p not significant). Vardenafil enhanced power Doppler ultrasound enables excellent visualization of the microvasculature associated with cancer and can improve the detection rate compared to contrast enhanced power Doppler ultrasound and the random technique. Copyright © 2011 American Urological

Stable Isotope Profiling of Internet-Sourced Viagra® and 'generic- Viagra' Tablets

NASA Astrophysics Data System (ADS)

Kemp, Helen; Meier-Augenstein, Wolfram

2013-04-01

Viagra® manufactured by Pfizer was the first prescription drug for the treatment of erectile dysfunction (ED), a condition that is estimated to affect 1 in 10 men at some stage in their lives (1). Viagra® contains the active pharmaceutical ingredient (API) sildenafil, as the citrate salt. Sildenafil, along with Tadalafil and Vardenafil belong to a class of drugs known as phosphodiesterase type 5 (PDE5) inhibitors. Since its first production in 1998, Viagra® has generated well in excess of 10 billion US dollars in sales (2) and with Pfizers' patent extended to April 2020 (3) it still remains the only sildenafil-based treatment option for sufferers of ED in the US. There are no legal 'generic-Viagra' formulations available in the US. However, formulations containing sildenafil citrate as API are widely available over the internet and often sold as 'generic Viagra'. These cheaper alternatives are often manufactured under less than ideal conditions with little or no QA/QC procedures in place. The World Health Organisation recognised the scale of the problem in its 2010 bulletin "Growing threat from counterfeit medicines" (4) and quotes a Dutch study cited in the International Journal of Clinical Practice in which from a cohort of 370 seized Viagra® samples, only 10 were genuine. We sourced a variety of tablets sold for the treatment of ED which claimed to have sildenafil citrate as API. Viagra®, 'generic-Viagra', Kamagra, Silagra and Filagra tablets were ordered via the internet and supplied from both UK-based pharmacies as well as overseas suppliers (Hong Kong, India, Vanuata). In this small-scale pilot study, we present results from bulk 2H/18O and 13C/15N stable isotope analysis performed on crushed tablets from 23 samples of internet-sourced tablets sold for the treatment of ED and purported to contain sildenafil citrate as API. References 1. www.healthcare.org.uk 2. www.moneynews.com 3. US Patent & trademark office (www.uspto.gov) 4. WHO bulletin 2010; 88:247-248

Comparison of phosphodiesterase type V inhibitors use in eight European cities through analysis of urban wastewater.

PubMed

Causanilles, Ana; Rojas Cantillano, Daniela; Emke, Erik; Bade, Richard; Baz-Lomba, Jose Antonio; Castiglioni, Sara; Castrignanò, Erika; Gracia-Lor, Emma; Hernández, Félix; Kasprzyk-Hordern, Barbara; Kinyua, Juliet; McCall, Ann-Kathrin; van Nuijs, Alexander L N; Plósz, Benedek G; Ramin, Pedram; Rousis, Nikolaos I; Ryu, Yeonsuk; Thomas, Kevin V; de Voogt, Pim

2018-04-02

In this work a step forward in investigating the use of prescription drugs, namely erectile dysfunction products, at European level was taken by applying the wastewater-based epidemiology approach. 24-h composite samples of untreated wastewater were collected at the entrance of eight wastewater treatment plants serving the catchment within the cities of Bristol, Brussels, Castellón, Copenhagen, Milan, Oslo, Utrecht and Zurich. A validated analytical procedure with direct injection of filtered aliquots by liquid chromatography-tandem mass spectrometry was applied. The target list included the three active pharmaceutical ingredients (sildenafil, tadalafil and vardenafil) together with (bio)transformation products and other analogues. Only sildenafil and its two human urinary metabolites desmethyl- and desethylsildenafil were detected in the samples with concentrations reaching 60 ng L -1 . The concentrations were transformed into normalized measured loads and the estimated actual consumption of sildenafil was back-calculated from these loads. In addition, national prescription data from five countries was gathered in the form of the number of prescribed daily doses and transformed into predicted loads for comparison. This comparison resulted in the evidence of a different spatial trend across Europe. In Utrecht and Brussels, prescription data could only partly explain the total amount found in wastewater; whereas in Bristol, the comparison was in agreement; and in Milan and Oslo a lower amount was found in wastewater than expected from the prescription data. This study illustrates the potential of wastewater-based epidemiology to investigate the use of counterfeit medication and rogue online pharmacy sales. Copyright © 2018. Published by Elsevier Ltd.

Evaluation of vardenafil for the treatment of subjective tinnitus: a controlled pilot study

PubMed Central

Mazurek, Birgit; Haupt, Heidemarie; Szczepek, Agnieszka J; Sandmann, Jörg; Gross, Johann; Klapp, Burghard F; Kiesewetter, Holger; Kalus, Ulrich; Stöver, Timo; Caffier, Philipp P

2009-01-01

Background Vardenafil (Levitra®) represents a potent and highly selective phosphodiesterase type 5 (PDE5) inhibitor, which is established for treatment of various diseases. There are several unpublished reports from patients stating that vardenafil has a considerable therapeutic effect on their concomitant tinnitus. This pilot study was conducted to specifically assess the effect of vardenafil in patients with chronic tinnitus. Methods This trial was based on a prospective, randomized, double-blind, placebo-controlled, parallel group design. Fourty-two consecutive subjects with mon- or binaural chronic tinnitus received 10 mg vardenafil (N = 21) or matching placebo tablets (N = 21) administered orally twice a day over a period of 12 weeks. Clinical examination and data acquisition took place at each visit: at baseline, after 4 weeks, after 12 weeks (end of treatment with study medication), and at non-medicated follow-up after 16 weeks. Assessment of clinical effectiveness was based on a standardized tinnitus questionnaire (TQ), the Short Form 36 health survey (SF-36), audiometric measurements (mode, pitch and loudness of tinnitus; auditory thresholds) and biomarkers of oxidative stress in patients' blood (malondialdehyde, protein carbonyl, homocysteine and total antioxidative status). Therapeutic efficacy was evaluated by comparison of subjective and objective parameters with baseline data between both treatment groups (ANCOVA). Results Vardenafil had no superior efficacy over placebo in the treatment of chronic tinnitus during this study. The primary efficacy criterion 'TQ total score' failed to demonstrate significant improvement compared to placebo. Subjective reports of TQ subscales and general quality of life areas (SF-36), objective audiometric examinations as well as investigated biomarkers for oxidative stress did not reveal any significant treatment effects. The safety profile was favorable and consistent with that in other vardenafil studies. Conclusion

Efficacy of vardenafil and influence on self-esteem and self-confidence in patients with severe erectile dysfunction.

PubMed

Martin-Morales, Antonio; Meijide, Fernando; García, Nicolás; Artes, Maite; Muñoz, Ana

2007-03-01

To assess the efficacy of vardenafil in a population of Spanish men with erectile dysfunction (ED), its influence on patients' self-esteem and self-confidence, and its effect on their quality of life. Efficacy was assessed by the International Index of Erectile Function-Erectile Function (IIEF-EF) domain, the Rosenberg Self-Esteem scale, the Johnson and McCoy Self-Confidence scale, the Medical Outcome Short Form (SF-36) scale, items 2 and 3 of the Sexual Encounter Profile questionnaire, and the Global Assessment Question (GAQ). Safety assessments included laboratory tests, physical exam, electrocardiogram, vital signs, and adverse events. This was a randomized, double-blind, multicenter, placebo-controlled study. After a 4-week treatment-free period, patients received flexible-dose vardenafil or placebo for 12 weeks. The initial dose was 10 mg, which could be titrated up to 20 mg or down to 5 mg at weeks 4 and 8. A total of 121 patients were included in the intention-to-treat analysis (61 on vardenafil and 60 on placebo). Of these, 16 in the vardenafil group and 14 in the placebo group had severe ED. There was a greater improvement in IIEF-EF domain score with vardenafil vs. placebo for all patients (score change of 10.9 vs. 1.6, respectively, P < 0.001) and for patients with severe ED (score change of 13.4 vs. 2.2, respectively, P = 0.011). A significant difference in favor of vardenafil was also observed for positive responses to the GAQ (73.8% vs. 25.0%, P < 0.001). After 12 weeks, vardenafil-treated patients with severe ED showed a significant improvement in their self-esteem compared with patients receiving placebo (change from baseline -1.51 vs. 3.54, respectively, P = 0.036). Vardenafil treatment was well tolerated. Vardenafil was highly effective for improving EF in all patients with ED, and resulted in significant improvements in self-esteem in patients with severe ED.

A phase 3 randomized placebo-controlled trial of tadalafil for Duchenne muscular dystrophy

PubMed Central

Sweeney, H. Lee; Finkel, Richard; McDonald, Craig M.; Byrne, Barry; Eagle, Michelle; Goemans, Nathalie; Vandenborne, Krista; Dubrovsky, Alberto L.; Topaloglu, Haluk; Miceli, M. Carrie; Furlong, Pat; Landry, John; Elashoff, Robert; Cox, David

2017-01-01

Objective: To conduct a randomized trial to test the primary hypothesis that once-daily tadalafil, administered orally for 48 weeks, lessens the decline in ambulatory ability in boys with Duchenne muscular dystrophy (DMD). Methods: Three hundred thirty-one participants with DMD 7 to 14 years of age taking glucocorticoids were randomized to tadalafil 0.3 mg·kg−1·d−1, tadalafil 0.6 mg·kg−1·d−1, or placebo. The primary efficacy measure was 6-minute walk distance (6MWD) after 48 weeks. Secondary efficacy measures included North Star Ambulatory Assessment and timed function tests. Performance of Upper Limb (PUL) was a prespecified exploratory outcome. Results: Tadalafil had no effect on the primary outcome: 48-week declines in 6MWD were 51.0 ± 9.3 m with placebo, 64.7 ± 9.8 m with low-dose tadalafil (p = 0.307 vs placebo), and 59.1 ± 9.4 m with high-dose tadalafil (p = 0.538 vs placebo). Tadalafil also had no effect on secondary outcomes. In boys >10 years of age, total PUL score and shoulder subscore declined less with low-dose tadalafil than placebo. Adverse events were consistent with the known safety profile of tadalafil and the DMD disease state. Conclusions: Tadalafil did not lessen the decline in ambulatory ability in boys with DMD. Further studies should be considered to confirm the hypothesis-generating upper limb data and to determine whether ambulatory decline can be slowed by initiation of tadalafil before 7 years of age. Clinicaltrials.gov identifier: NCT01865084. Classification of evidence: This study provides Class I evidence that tadalafil does not slow ambulatory decline in 7- to 14-year-old boys with Duchenne muscular dystrophy. PMID:28972192

A phase 3 randomized placebo-controlled trial of tadalafil for Duchenne muscular dystrophy.

PubMed

Victor, Ronald G; Sweeney, H Lee; Finkel, Richard; McDonald, Craig M; Byrne, Barry; Eagle, Michelle; Goemans, Nathalie; Vandenborne, Krista; Dubrovsky, Alberto L; Topaloglu, Haluk; Miceli, M Carrie; Furlong, Pat; Landry, John; Elashoff, Robert; Cox, David

2017-10-24

To conduct a randomized trial to test the primary hypothesis that once-daily tadalafil, administered orally for 48 weeks, lessens the decline in ambulatory ability in boys with Duchenne muscular dystrophy (DMD). Three hundred thirty-one participants with DMD 7 to 14 years of age taking glucocorticoids were randomized to tadalafil 0.3 mg·kg -1 ·d -1 , tadalafil 0.6 mg·kg -1 ·d -1 , or placebo. The primary efficacy measure was 6-minute walk distance (6MWD) after 48 weeks. Secondary efficacy measures included North Star Ambulatory Assessment and timed function tests. Performance of Upper Limb (PUL) was a prespecified exploratory outcome. Tadalafil had no effect on the primary outcome: 48-week declines in 6MWD were 51.0 ± 9.3 m with placebo, 64.7 ± 9.8 m with low-dose tadalafil ( p = 0.307 vs placebo), and 59.1 ± 9.4 m with high-dose tadalafil ( p = 0.538 vs placebo). Tadalafil also had no effect on secondary outcomes. In boys >10 years of age, total PUL score and shoulder subscore declined less with low-dose tadalafil than placebo. Adverse events were consistent with the known safety profile of tadalafil and the DMD disease state. Tadalafil did not lessen the decline in ambulatory ability in boys with DMD. Further studies should be considered to confirm the hypothesis-generating upper limb data and to determine whether ambulatory decline can be slowed by initiation of tadalafil before 7 years of age. NCT01865084. This study provides Class I evidence that tadalafil does not slow ambulatory decline in 7- to 14-year-old boys with Duchenne muscular dystrophy. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Avanafil for the treatment of erectile dysfunction: initial data and clinical key properties.

PubMed

Kedia, George T; Uckert, Stefan; Assadi-Pour, Farhang; Kuczyk, Markus A; Albrecht, Knut

2013-02-01

Orally active, selective inhibitors of phosphodiesterase type 5 (PDE 5, cyclic GMP PDE), such as sildenafil, tadalafil and vardenafil, are currently the first-choice treatment options for the clinical management of erectile dysfunction (ED) of various etiologies and severities. However, a significant number of patients remain dissatisfied with the available therapies due a lack of efficacy or discomfort arising from adverse events. Several new PDE5 inhibitors, among which are avanafil (TA-1790), lodenafil, mirodenafil, udenafil, SLX-2101, JNJ-10280205 and JNJ-10287069, have recently been approved and introduced into the market or are in the final stages of their clinical development. Avanafil (marketed in the US under the brand name STENDRA(™)) has been developed by VIVUS Inc. (Mountain View, CA, USA) and has recently received approval from the US Food and Drug Administration (FDA) for use in the treatment of male ED. The drug has demonstrated improved selectivity for PDE5, is rapidly absorbed after oral administration with a fast onset of action and a plasma half-life that is comparable to sildenfil and vardenafil. In phase II and phase III clinical trials that included a large number of patients, avanafil has been shown to be effective and well tolerated. Owing to its favorable pharmacodynamic and pharmacokinetic profile, avanafil is considered as a promising new option in the treatment of ED. The present article summarizes the initial data and clinical key properties of avanafil.

Avanafil for the treatment of erectile dysfunction: initial data and clinical key properties

PubMed Central

Ückert, Stefan; Assadi-Pour, Farhang; Kuczyk, Markus A.; Albrecht, Knut

2013-01-01

Orally active, selective inhibitors of phosphodiesterase type 5 (PDE 5, cyclic GMP PDE), such as sildenafil, tadalafil and vardenafil, are currently the first-choice treatment options for the clinical management of erectile dysfunction (ED) of various etiologies and severities. However, a significant number of patients remain dissatisfied with the available therapies due a lack of efficacy or discomfort arising from adverse events. Several new PDE5 inhibitors, among which are avanafil (TA-1790), lodenafil, mirodenafil, udenafil, SLX-2101, JNJ-10280205 and JNJ-10287069, have recently been approved and introduced into the market or are in the final stages of their clinical development. Avanafil (marketed in the US under the brand name STENDRA™) has been developed by VIVUS Inc. (Mountain View, CA, USA) and has recently received approval from the US Food and Drug Administration (FDA) for use in the treatment of male ED. The drug has demonstrated improved selectivity for PDE5, is rapidly absorbed after oral administration with a fast onset of action and a plasma half-life that is comparable to sildenfil and vardenafil. In phase II and phase III clinical trials that included a large number of patients, avanafil has been shown to be effective and well tolerated. Owing to its favorable pharmacodynamic and pharmacokinetic profile, avanafil is considered as a promising new option in the treatment of ED. The present article summarizes the initial data and clinical key properties of avanafil. PMID:23372609

Phosphodiesterase inhibitors in clinical urology.

PubMed

Ückert, Stefan; Kuczyk, Markus A; Oelke, Matthias

2013-05-01

To date, benign diseases of the male and female lower urinary and genital tract, such as erectile dysfunction, bladder overactivity, lower urinary tract symptomatology secondary to benign prostatic hyperplasia and symptoms of female sexual dysfunction (including arousal and orgasmic disorders), can be therapeutically approached by influencing the function of the smooth musculature of the respective tissues. The use of isoenzyme-selective phosphodiesterase (PDE) inhibitors is considered a great opportunity to treat various diseases of the human urogenital tract. PDE inhibitors, in particular the PDE5 (cyclic GMP PDE) inhibitors avanafil, lodenafil, sildenafil, tadalafil, udenafil and vardenafil, are regarded as efficacious, having a fast onset of drug action and an improved effect-to-adverse event ratio, combining a high response rate with the advantage of an on-demand intake. The purpose of this review is to summarize recent as well as potential future indications, namely, erectile dysfunction, Peyronie's disease, overactive bladder, urinary stone disease, lower urinary tract symptomatology secondary to benign prostatic hyperplasia and premature ejaculation, for the use of PDE inhibitors in clinical urology.

Stability of an extemporaneously prepared tadalafil suspension.

PubMed

Pettit, Rebecca S; Johnson, Cary E; Caruthers, Regine L

2012-04-01

The stability of an extemporaneously prepared tadalafil oral suspension was studied. An oral suspension of tadalafil 5 mg/mL was prepared by thoroughly grinding 15 20-mg tadalafil tablets in a glass mortar. Thirty milliliters of Ora-Plus and 30 mL of Ora-Sweet were mixed and added to the powder to make a final volume of 60 mL. Three identical samples of the formulation were prepared and placed in 2-oz amber plastic bottles with child-resistant caps and stored at room temperature (23-25 °C). A 1-mL sample was withdrawn from each of the three bottles with a micropipette immediately after preparation and at 7, 14, 28, 57, and 91 days. After double dilution (1:10 and 0.1:5 v/v) to an expected concentration of 10 μg/mL with methanol and mobile phase, respectively, the samples were assayed in duplicate using stability-indicating high-performance liquid chromatography. The samples were visually examined for any color change and evaluated for pH changes on each day of analysis. Taste evaluation was performed at the beginning and end of the study. Stability was defined as the retention of at least 90% of the initial concentration. At least 99% of the initial tadalafil concentration remained throughout the 91-day study period. There were no detectable changes in color, odor, taste, and pH, and no visible microbial growth was observed in any sample. An extemporaneously prepared suspension of tadalafil 5 mg/mL in a 1:1 mixture of Ora-Plus and Ora-Sweet was stable for at least 91 days when stored in amber plastic bottles at room temperature.

Dissolution enhancement of tadalafil by liquisolid technique.

PubMed

Lu, Mei; Xing, Haonan; Yang, Tianzhi; Yu, Jiankun; Yang, Zhen; Sun, Yanping; Ding, Pingtian

2017-02-01

This study aimed to enhance the dissolution of tadalafil, a poorly water-soluble drug by applying liquisolid technique. The effects of two critical formulation variables, namely drug concentration (17.5% and 35%, w/w) and excipients ratio (10, 15 and 20) on dissolution rates were investigated. Pre-compression tests, including particle size distribution, flowability determination, Fourier transform infrared (FT-IR), differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and scanning electron microscopy (SEM), were carried out to investigate the mechanism of dissolution enhancement. Tadalafil liquisolid tablets were prepared and their quality control tests, dissolution study, contact angle measurement, Raman mapping, and storage stability test were performed. The results suggested that all the liquisolid tablets exhibited significantly higher dissolution rates than the conventional tablets and pure tadalafil. FT-IR spectrum reflected no drug-excipient interactions. DSC and XRD studies indicated reduction in crystallinity of tadalafil, which was further confirmed by SEM and Raman mapping outcomes. The contact angle measurement demonstrated obvious increase in wetting property. Taken together, the reduction of particle size and crystallinity, and the improvement of wettability were the main mechanisms for the enhanced dissolution rate. No significant changes were observed in drug crystallinity and dissolution behavior after storage based on XRD, SEM and dissolution results.

cGMP-Phosphodiesterase Inhibition Enhances Photic Responses and Synchronization of the Biological Circadian Clock in Rodents

PubMed Central

Plano, Santiago A.; Agostino, Patricia V.; de la Iglesia, Horacio O.; Golombek, Diego A.

2012-01-01

The master circadian clock in mammals is located in the hypothalamic suprachiasmatic nuclei (SCN) and is synchronized by several environmental stimuli, mainly the light-dark (LD) cycle. Light pulses in the late subjective night induce phase advances in locomotor circadian rhythms and the expression of clock genes (such as Per1-2). The mechanism responsible for light-induced phase advances involves the activation of guanylyl cyclase (GC), cGMP and its related protein kinase (PKG). Pharmacological manipulation of cGMP by phosphodiesterase (PDE) inhibition (e.g., sildenafil) increases low-intensity light-induced circadian responses, which could reflect the ability of the cGMP-dependent pathway to directly affect the photic sensitivity of the master circadian clock within the SCN. Indeed, sildenafil is also able to increase the phase-shifting effect of saturating (1200 lux) light pulses leading to phase advances of about 9 hours, as well as in C57 a mouse strain that shows reduced phase advances. In addition, sildenafil was effective in both male and female hamsters, as well as after oral administration. Other PDE inhibitors (such as vardenafil and tadalafil) also increased light-induced phase advances of locomotor activity rhythms and accelerated reentrainment after a phase advance in the LD cycle. Pharmacological inhibition of the main downstream target of cGMP, PKG, blocked light-induced expression of Per1. Our results indicate that the cGMP-dependent pathway can directly modulate the light-induced expression of clock-genes within the SCN and the magnitude of light-induced phase advances of overt rhythms, and provide promising tools to design treatments for human circadian disruptions. PMID:22590651

Cardiac function and tadalafil used for treating fetal growth restriction in pregnant women without cardiovascular disease.

PubMed

Tanaka, Kayo; Tanaka, Hiroaki; Maki, Shintaro; Kubo, Michiko; Nii, Masafumi; Magawa, Shoichi; Hatano, Fumi; Tsuji, Makoto; Osato, Kazuhiro; Kamimoto, Yuki; Umekawa, Takashi; Ikeda, Tomoaki

2018-02-20

The aim of the present study was to evaluate tadalafil for the treatment of fetal growth restriction (FGR) and the cardiac function in pregnant women without cardiovascular disease who used tadalafil for this reason. We examined nine pregnant women without cardiovascular disease who were using tadalafil to treat FGR. Maternal heart rate, systolic blood pressure (BP), and echocardiographic findings were assessed before and after tadalafil use. Diastolic BP was lower after compared to that before using tadalafil, but the difference was not significant. Echocardiographic findings were not significantly different before and after tadalafil use. Tadalafil did not adversely affect pregnant women without cardiovascular disease and was considered acceptable for use since it did not affect the mother's cardiac function.

Vardenafil improves ejaculation success rates and self-confidence in men with erectile dysfunction due to spinal cord injury.

PubMed

Giuliano, Francois; Rubio-Aurioles, Eusebio; Kennelly, Michael; Montorsi, Francesco; Kim, Edward D; Finkbeiner, Alex E; Pommerville, Peter J; Colopy, Michael W; Wachs, Barton H

2008-04-01

Multicenter, double-blind, placebo-controlled, parallel-group study. To assess the effect of the oral phosphodiesterase type-5 inhibitor, vardenafil, on ejaculation rates and self-confidence in men with spinal cord injury (SCI). Spinal command of male sexual functions is often seriously impaired by traumatic spinal cord injury (SCI). A high proportion of men with SCI cannot ejaculate during sexual intercourse. SCI-related ejaculatory disorders are often responsible for male infertility. Sexual dysfunction associated with SCI can also affect men's self-confidence. In this 12-week study, 418 men aged >or=18 years with erectile dysfunction >6 months resulting from a traumatic SCI were randomized to vardenafil (n = 207) or placebo (n = 211) 10 mg for 4 weeks, then maintained or titrated to 5 or 20 mg at weeks 4 and 8. Assessments included questions of the International Index of Erectile Function (IIEF) about ejaculation success and orgasmic perception; the Global Confidence Question; and quality-of-life scales to measure psychological well-being, self-esteem, depression, and mental health status. Overall per patient ejaculation success rates were significantly greater with vardenafil than placebo over 12 weeks of treatment (19% vs. 10%; P < 0.001). At last observation carried forward, the IIEF "orgasmic function" score increased from 2.9 at baseline to 4.0 for vardenafil and from 3.0 at baseline to 3.4 for placebo. Sixteen percent of men receiving vardenafil and 8% receiving placebo felt orgasm "almost always" or "always" at weeks 8-12, compared with 4% and 6%, respectively, at baseline. Significant improvements in confidence scores were observed with vardenafil compared with placebo (P < 0.0001). There were no clinically significant differences between vardenafil and placebo in the quality-of-life measures at the study endpoint, but these had been in the normal range at baseline. Vardenafil significantly improved ejaculation and self-confidence in men with erectile

Efficacy and tolerability of vardenafil for treatment of erectile dysfunction in patient subgroups.

PubMed

Porst, Hartmut; Young, Jay M; Schmidt, Abraham C; Buvat, Jacques

2003-09-01

To assess whether vardenafil would improve erectile function irrespective of etiology, baseline severity, or patient age. The consistency of the response over time was also evaluated. A multicenter, randomized, double-blind, placebo-controlled at-home study of vardenafil treatment (5, 10, and 20 mg) was performed. This secondary analysis compared the mean International Index of Erectile Function (IIEF) erectile function domain scores of various subgroups at 12 weeks of treatment. These populations included organic, psychogenic, or mixed etiologies; mild, moderate, or severe baseline severity; and four age groups (younger than 45, 45 to 55, 56 to 65, and older than 65 years). In addition, all IIEF domains were compared at sequential 4-week periods, before and during treatment. In the 580 men of the intent-to-treat population, the mean erectile function domain scores were statistically greater than placebo, irrespective of etiology, baseline severity, or age. This was seen at all dosages. Compared with placebo, vardenafil statistically improved the IIEF domain scores of erectile function, orgasmic function, intercourse satisfaction, and overall satisfaction after 4 weeks of treatment, and these improvements were maintained for 12 weeks. The rates of the most common adverse events (headache, flushing, and dyspepsia) were either constant or declined over time; they were generally mild to moderate and transient in nature. Vardenafil improved erectile function regardless of the general etiology, baseline severity of erectile dysfunction, or patient age. Improvements in erectile function and other key IIEF domains were consistently seen throughout the study.

Randomised Trial of CPAP and Vardenafil on Erectile and Arterial Function in Men with Obstructive Sleep Apnea and Erectile Dysfunction.

PubMed

Melehan, Kerri L; Hoyos, Camilla M; Hamilton, Garun S; Wong, Keith K; Yee, Brendon J; McLachlan, Rob I; O'Meagher, Shamus; Celermajer, David; Ng, Martin K; Grunstein, Ronald R; Liu, Peter Y

2018-02-01

Erectile function is important for life satisfaction and is often impaired in men with obstructive sleep apnea (OSA). Uncontrolled studies show that treating OSA with continuous positive airway pressure (CPAP) improves erectile function. Phosphodiesterase type 5 inhibitors (e.g. vardenafil) are the first-line therapy for erectile dysfunction (ED), but may worsen OSA. To assess the effects of CPAP and vardenafil on ED. Sixty one men with moderate-to-severe OSA and ED were randomised to 12 weeks of CPAP or sham CPAP, and 10mg daily vardenafil or placebo, in a 2x2 factorial design. International Index of Erectile Function (primary endpoint), treatment and relationship satisfaction, sleep related erections, sexual function, endothelial function, arterial stiffness, quality of life, and sleep-disordered breathing. CPAP increased the frequency of sleep-related-erections, overall sexual satisfaction, and arterial stiffness but did not change erectile function or treatment satisfaction or relationship satisfaction. Vardenafil did not alter erectile function, endothelial function, arterial stiffness or sleep disordered breathing, but did improve overall self-esteem and relationship satisfaction, other aspects of sexual function and treatment satisfaction. Adherent CPAP improved erectile function, sexual desire, overall sexual, self-esteem and relationship, and treatment satisfaction, as well as sleepiness, and quality of life. Adherent vardenafil use did not consistently change nocturnal erection quality. CPAP improves overall sexual satisfaction, sleep related erections, and arterial stiffness. Low dose daily vardenafil improves certain aspects of sexual function, and did not worsen OSA. Adherent CPAP or vardenafil use further improves ED and quality of life. Copyright © 2018 Endocrine Society

Inhaled sildenafil as an alternative to oral sildenafil in the treatment of pulmonary arterial hypertension (PAH).

PubMed

Rashid, Jahidur; Patel, Brijeshkumar; Nozik-Grayck, Eva; McMurtry, Ivan F; Stenmark, Kurt R; Ahsan, Fakhrul

2017-03-28

The practice of treating PAH patients with oral or intravenous sildenafil suffers from the limitations of short dosing intervals, peripheral vasodilation, unwanted side effects, and restricted use in pediatric patients. In this study, we sought to test the hypothesis that inhalable poly(lactic-co-glycolic acid) (PLGA) particles of sildenafil prolong the release of the drug, produce pulmonary specific vasodilation, reduce the systemic exposure of the drug, and may be used as an alternative to oral sildenafil in the treatment of PAH. Thus, we prepared porous PLGA particles of sildenafil using a water-in-oil-in-water double emulsion solvent evaporation method with polyethyleneimine (PEI) as a porosigen and characterized the formulations for surface morphology, respirability, in-vitro drug release, and evaluated for in vivo absorption, alveolar macrophage uptake, and safety. PEI increased the particle porosity, drug entrapment, and produced drug release for 36h. Fluorescent particles showed reduced uptake by alveolar macrophages. The polymeric particles were safe to rat pulmonary arterial smooth muscle cell and to the lungs, as evidenced by the cytotoxicity assay and analyses of the injury markers in the bronchoalveolar lavage fluid, respectively. Intratracheally administered sildenafil particles elicited more pulmonary specific and sustained vasodilation in SUGEN-5416/hypoxia-induced PAH rats than oral, intravenous, or intratracheal plain sildenafil did, when administered at the same dose. Overall, true to the hypothesis, this study shows that inhaled PLGA particles of sildenafil can be administered, as a substitute for oral form of sildenafil, at a reduced dose and longer dosing interval. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of sildenafil on cardiac repolarization.

PubMed

Chiang, Chern-En; Luk, Hsiang-Ning; Wang, Tsui-Min; Ding, Philip Yu-An

2002-08-01

Sudden death has occasionally been reported in patients taking sildenafil. The objective of this study was to investigate the effect of sildenafil on cardiac repolarization. We used conventional microelectrode recording technique in isolated guinea pig papillary muscles and canine Purkinje fibers, whole-cell patch clamp techniques in guinea pig ventricular myocytes, and in vivo ECG measurements in guinea pigs. Action potential duration at 90% repolarization (APD(90)) was not affected by sildenafil in the therapeutic ranges (< or =1 microM), but shortened by higher concentration (> or =10 microM) in both guinea pig papillary muscles and canine Purkinje fibers. D-Sotalol prolonged APD(90) in the same preparations with concentrations > or =1 microM in a reverse frequency-dependent manner. Co-administration of sildenafil (10 and 30 microM) abolished the APD-prolonging effects of D-sotalol (30 microM) and amiodarone (100 microM). Sildenafil, with concentrations up to 30 microM, had no significant effect on both the rapid (I(Kr)) and the slow (I(Ks)) components of the delayed rectifier potassium currents in guinea pig ventricular myocytes. Sildenafil dose-dependently blocked L-type Ca(2+) current (I(Ca,L)), but had no effect on persistent Na(+) current in guinea pig ventricular myocytes. ECG recordings in intact guinea pigs revealed significant shortening of QTc interval by sildenafil (10 and 30 mg/kg orally). The QT-prolonging effects by D,L-sotalol (50 mg/kg) and amiodarone (100 mg/kg) were abolished by sildenafil (30 mg/kg). Sildenafil does not prolong cardiac repolarization. Instead, in supra-therapeutic concentrations, it accelerates cardiac repolarization, presumably through its blocking effect on I(Ca,L).

Sildenafil Citrate in Fetal Growth Restriction

PubMed Central

Panda, Subrat; Das, Ananya; Md Nowroz, Hossain

2014-01-01

Background Pregnancies with early onset fetal growth restriction have poor perinatal outcome. Sildenafil citrate (PDE -5 inhibitor) as a vasodilator increases utero-placental blood flow and potentiates fetal growth. Case Presentation In this study, a case was examined and Sildenafil was administered for her. It was found that Sildenafil improved the uterine blood flow with a favorable fetal outcome at delivery. Conclusion Sildenafil, as a vasodilator has emerged as a potential management option in the treatment of Intra Uterine Growth Retardation (IUGR) and preeclampsia by later normalization in velocimetric profile. PMID:25202677

Tadalafil reversal of sexual dysfunction caused by serotonin enhancing medications in women.

PubMed

Ashton, Adam Keller; Weinstein, Wendy

2006-01-01

Sexual dysfunction is a common side effect of many antidepressants, especially those that increase serotonin. Many strategies have been reported to assist patients in minimizing impairment, with variable degrees of success. One of the newer approaches is to augment with phosphodiesterase type-5 inhibitors. Our report using the most recently released agent in this class, tadalafil is the first demonstrating potential benefit in women. We report here of three women who derived benefit from using 20 mg of tadalafil before anticipated sexual activity to reverse medication-induced sexual dysfunction. Tadalafil utility was maintained over time and was well tolerated.

Cardiovascular risk and sildenafil.

PubMed

Kloner, R A

2000-07-20

Sildenafil citrate is the first oral agent approved for the treatment of erectile dysfunction (ED); other oral agents are in the process of development. Because the mechanism of action of many of these agents involves vasodilation, there is a potential for interaction with the cardiovascular system. Sildenafil inhibits phosphodiesterase-5 (PDE-5) which is found in the corpus cavernosum and in the systemic vasculature. Sildenafil causes a mild decrease in systemic arterial pressure ( approximately -8/-5.5 mm Hg); it causes a synergistic and often major decrease in systemic arterial pressure in the presence of organic nitrates (nitric oxide donors). Sildenafil is therefore contraindicated in patients taking organic nitrates. A review was made of clinical trials in populations of men with (1) erectile dysfunction; (2) chronic stable ischemic heart disease and erectile dysfunction; and (3) hypertension and erectile dysfunction. This review showed that sildenafil was effective and not associated with an increase in serious cardiovascular adverse events, myocardial infarction (MI), or death compared with placebo. Although there have been spontaneous reports of death among men using sildenafil, there are limitations to spontaneous-event reporting. In addition. the numbers of such reports are well below the expected numbers of deaths when considering the number of men who have received prescriptions for sildenafil and their age and cardiovascular risk factor profile. Because there is a small but finite risk of having a cardiac event with sexual activity, physicians should discuss with their cardiac patients the risks of sexual activity before prescribing any treatment for ED. In addition, they should evaluate their patients' cardiac status when considering the safety of administering any ED treatment that may have systemic vasodilatory properties and can potentially lower blood pressure. In some cases, exercise treadmill testing may be warranted to determine whether ED

[Effects of sildenafil citrate on mice hearing].

PubMed

Luo, Xiaoqin; Guo, Xuyao; Chen, Lin; Chen, Xiaohong; Zhang, Xueyuan; Yuan, Wei

2014-06-01

The purpose of this investigation was to study the effects of the Sildenafil citrate on mice hearing. Seven-week-old adult male Kunming mice were used. The mice were randomly divided into four groups with 10 mice in each group.Sildenafil groups were orally administered daily with sildenafil [0.1 mg/(kg·d), 1 mg/(kg·d), 10 mg/(kg·d)] and control group was orally administered with normal saline. Then mice were tested for auditory brainstem response (ABR) to observe the changes of ABR's thresholds at before administration and 1, 5, 10, 15, 20 day afterwards. The mice basilar membrane samples were studied by immunofluorescent labeling.High performance liquid chromatography was used for determination the concentration of sildenafil in endolymph of mice cochlea. Statistical analysis was performed using SPSS 13.0. After 30 min following administration, the Sildenafil in endolymph of mice cochlear could be assayed by high performance liquid chromatography, and it was dose-related.Sildenafil increased the hearing thresholds with the time of administration. Hearing thresholds increased significantly in the sildenafil group at 20 d compared to the control group (P < 0.05). After administered high dose of Sildenafil, on the 20th day, the ABR thresholds average threshold was (60.0 ± 10.0) dBnHL, and the control group was (14.5 ± 6.0) dBnHL.Hair cells damages in the base ring of cochlea could be observed in experimental group in a concentration-dependent manner. Sildenafil can pass through blood-labyrinth barrier to the inner ear, and doses of sildenafil administration can induce hearing impairment in mice.

Tadalafil - a therapeutic option in the management of BPH-LUTS.

PubMed

Carson, C C; Rosenberg, M; Kissel, J; Wong, D G

2014-01-01

Men with signs of benign prostatic hyperplasia (BPH) may experience lower urinary tract symptoms (LUTS) such as urinary frequency, urgency, intermittence, nocturia, straining, incomplete emptying or a weak urinary stream. The effective management of LUTS suggestive of BPH (BPH-LUTS) requires careful consideration of several factors, including the severity of a patient's symptoms, concurrent or other coexisting medical conditions, the ability to improve symptoms and impact quality of life (QOL), as well as the potential side effects of available treatment options. Several clinical studies have assessed phosphodiesterase type 5 (PDE5) inhibitors in reducing LUTS; however, tadalafil is the only PDE5 inhibitor approved for the treatment of signs and symptoms of BPH, as well as in men with both erectile dysfunction (ED) and the signs and symptoms of BPH. This review examined articles that assessed tadalafil in patients with signs and symptoms of BPH, with or without erectile dysfunction (ED), which led to regulatory approval in the United States and Europe. In dose-ranging and confirmatory studies, results demonstrate that tadalafil significantly improved total International Prostate Symptom Score (IPSS) following 12 weeks of treatment with once daily tadalafil 5 mg. Statistically significant improvements in Benign Prostatic Hyperplasia Impact Index (BII), IPSS subscores, IPSS QOL and International Index of Erectile Function (IIEF) were also observed. Improvement in urinary symptoms occurred regardless of age, previous treatment with an α1 -adrenergic blocker, BPH-LUTS severity at baseline or ED status. While tadalafil is most frequently recognised as a standard treatment option for men with ED, it also represents a well-tolerated and effective treatment option in men with moderate to severe BPH-LUTS. © 2013 John Wiley & Sons Ltd.

Effect of Tadalafil on Seizure Threshold and Activity of Antiepileptic Drugs in Three Acute Seizure Tests in Mice.

PubMed

Socała, Katarzyna; Nieoczym, Dorota; Pieróg, Mateusz; Wyska, Elżbieta; Szafarz, Małgorzata; Doboszewska, Urszula; Wlaź, Piotr

2018-02-09

Tadalafil, a selective phosphodiesterase type 5 inhibitor, is a long-acting oral agent for the treatment of erectile dysfunction of multiple etiologies. Although generalized tonic-clonic seizures were reported in a healthy man after taking tadalafil, the influence of tadalafil on seizure susceptibility has not been studied so far. Therefore, the aim of the present study was to investigate the effect of tadalafil on seizure threshold as well as on the activity of some first- and second-generation antiepileptic drugs in three acute seizure tests in mice. The obtained results showed that tadalafil, at the highest dose tested (20 mg/kg), significantly decreased the threshold for the first myoclonic twitch in the intravenous pentylenetetrazole (i.v. PTZ) seizure test. It did not affect the threshold for generalized clonic seizure and forelimb tonus in the i.v. PTZ, for tonic hindlimb extension in the maximal electroshock seizure threshold test, and for psychomotor seizure in the 6-Hz-induced seizure threshold test. Tadalafil did not alter the anticonvulsant activity of any of the studied antiepileptic drugs in electrically induced seizure tests. Interestingly, tadalafil potentiated the anticonvulsant activity of clonazepam and decreased the anticonvulsant activity of oxcarbazepine in the i.v. PTZ test. These interactions were pharmacodynamic in nature, as tadalafil did not alter clonazepam and oxcarbazepine concentrations both in serum and brain tissue. Furthermore, neither tadalafil alone nor its combinations with the studied antiepileptic drugs produced any significant impairment of motor coordination (assessed in the chimney test), muscular strength (investigated in the grip-strength test), and long-term memory (assessed in the passive avoidance task). In conclusion, tadalafil may increase the risk of myoclonic seizure and decrease the anticonvulsant efficacy of oxcarbazepine. Further studies are warranted to evaluate the safety of tadalafil usage in patients with

Tadalafil inclusion in microporous silica as effective dissolution enhancer: optimization of loading procedure and molecular state characterization.

PubMed

Mehanna, Mohammed M; Motawaa, Adel M; Samaha, Magda W

2011-05-01

Tadalafil is an efficient drug used to treat erectile dysfunction characterized by poor water solubility, which has a negative influence on its bioavailability. Utilization of microporous silica represents an effective and facile technology to increase the dissolution rate of poorly soluble drugs. Our strategy involved directly introducing tadalafil as guest molecule into microporous silica as host material by incipient wetness impregnation method. To optimize tadalafil inclusion, response surface methodology (RSM) using 3(3) factorial design was utilized. Furthermore, to investigate the molecular state of tadalafil, Fourier-transform infrared spectroscopy, differential scanning calorimetery, thermal gravimetrical analysis, nitrogen adsorption, and powder X-ray diffraction (PXRD) were carried out. The results obtained pointed out that the quantity of microporous silica was the predominant factor that increased the loading efficiency. For the optimized formula, the loading efficiency was 42.50 wt %. Adsorption-desorption experiments indicated that tadalafil has been introduced into the micropores. Powder XRD and differential scanning calorimetry analyses revealed that tadalafil is arranged in amorphous form. In addition, the dissolution rate of tadalafil from the microporous silica was faster than that of free drug. Amorphous tadalafil occluded in microporous silica did not crystallize over 3 months. These findings contributed in opening a new strategy concerning the utilization of porous silica for the dissolution rate enhancement. Copyright © 2010 Wiley-Liss, Inc.

Sildenafil

MedlinePlus

... Revatio) is the best medication to treat a child's condition. Sildenafil is in a class of medications ... eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. ...

Sorption and Transport of Sildenafil in Natural Soils

NASA Astrophysics Data System (ADS)

Boudinot, F. G.; Vulava, V. M.

2013-12-01

Pharmaceutical Chemicals (PCs) mainly enter our ecosystems from discharges of treated wastewater and have direct effects on the ecological health of that area. Sildenafil citrate (Viagra) is one such PC, whose presence has been reported in stream waters. Although one study has shown that sildenafil is not harmful in bacterial and fungal environments, there remains much unknown about its fate elsewhere in ecosystems. Sildenafil is a complex organic molecule with two amino functional groups that result in pKa's of 7.27 and 5.97. It also has a high solubility of 3.5 g/L. Given that sildenafil consumption (and concurrently disposal) is on the rise, it is essential that its behavior in the natural environment be better understood. The goal of this study was to quantify the sorption and transport behavior of sildenafil in differing natural soils with varying compositions. Pristine A- and B- horizon soil samples from several soil series were collected in a managed forest near Charleston, SC and used for these studies. The soils were characterized for physical and chemical properties: soil organic matter content ranged between 0.6-7.6%, clay content between 6-20%, and soil pH between 4-5. These soils were then used to perform kinetic reaction, sorption, and column transport experiments. Batch kinetic experiments showed a fast reaction rate in both clay-rich and organic-rich soils and an equilibration time of less than 24 hours. Batch reactor sorption experiments provided data for sorption isotherms (plot of sildenafil in solution, C vs. sildenafil sorbed in soil, q) which were nonlinear. The isotherms were fit using Freundlich model (q=KfCn, where Kf and n are fitting parameters). Sildenafil sorbed more strongly to clay-rich soils compared with organic-rich soils with less clay. It is hypothesized that permanent negative charge on clay mineral surfaces form ionic bonds with positively charged amines in sildenafil in acidic pHs. Transport experiments were conducted using

Sildenafil Increases Sympathetically Mediated Vascular Tone in Humans

PubMed Central

2013-01-01

BACKGROUND Sildenafil, a selective phosphodiesterase-type-5 (PDE-5) inhibitor, produces vasodilation that improves erectile dysfunction and pulmonary hypertension. Sildenafil could also cause baroreflex sympathetic activation that would enhance vascular tone and oppose direct vasodilation. We tested the hypothesis that sildenafil administration increases sympathetically mediated vascular tone in healthy middle-aged men. METHODS We randomized 9 healthy, middle-aged, male volunteers (mean age 45±2 years) in a double-blind, crossover fashion to receive a single oral dose of sildenafil 100mg or placebo on 2 separate study days. Hemodynamics and forearm blood flow responses were measured at baseline, at 30 and 45 minutes after study drug administration, and then during intra-arterial infusions of vasoactive drugs. After sildenafil and placebo administration, intrabrachial medications were infused to test forearm alpha receptor sensitivity (norepinephrine), cyclic-AMP–mediated vasodilation (isoproterenol), and sympathetically mediated vascular tone (phentolamine) (adenosine was a control vasodilator). Blood samples were taken before and 60 minutes after study drug administration and at the end of the intrabrachial infusions for measurement of plasma norepinephrine concentrations. RESULTS Forearm vascular responses to norepinephrine, isoproterenol, and adenosine were not different after placebo and sildenafil administration. Percentage reduction in forearm vascular resistance during phentolamine was significantly lower after sildenafil than placebo (−73% ± 3% vs −63% ± 3%; P = 0.0002). Sildenafil significantly increased plasma norepinephrine compared with placebo 60 minutes after study drug administration and at the end of the study session (P = 0.02). CONCLUSIONS Sildenafil increased sympathetically mediated vascular tone in middle-aged healthy men. Alpha-adrenergic–mediated vasoconstriction may offset vasodilation during PDE-5 inhibition and may explain the

Bioequivalence of 2 Formulations of Sildenafil Oral Soluble Film 100 mg and Sildenafil Citrate (Viagra) 100 mg Oral Tablets in Healthy Male Volunteers.

PubMed

Dadey, Eric

Sildenafil citrate tablets (VIAGRA; Pfizer Inc) have been used since 1998 as an oral therapy for the treatment of erectile dysfunction. However, in some cases, patients may have difficulty in swallowing tablets, and the need to use water to aid in the oral administration of the tablets has the potential to interrupt the sexual encounter, reduce spontaneity, and therefore decrease the quality of the experience. Two oral soluble film (OSF) formulations of sildenafil were developed using MonoSol Rx's proprietary PharmFilm technology. Both films were formulated to dissolve rapidly on the tongue, thereby releasing the drug into the oral cavity, whereupon it is swallowed without the use of water. From a patient perspective, it is anticipated that the film formulations of sildenafil citrate will provide a more compliant and discreet dosage form. The purpose of this clinical study was to compare the bioequivalence of the 2 sildenafil OSF 100 mg formulations (MonoSol Rx, LLC) with the sildenafil citrate 100 mg tablets. The design was a single-dose, randomized, open-label, 3-period, 6-sequence, 3-treatment, single-center, crossover study conducted in 18 healthy, nonsmoking male volunteers under fasting conditions, with each treatment period separated by a 7-day washout period. Plasma sildenafil concentrations were measured predose and then periodically to 24 hours after dosing. The 90% confidence intervals for plasma sildenafil AUC0-t, AUC0-∞, and Cmax for both sildenafil OSF formulations as compared with sildenafil citrate tablets were all within the 80%-125% range, indicating bioequivalence of both film formulations to sildenafil citrate tablets. Overall, the demonstrated bioequivalence coupled with the performance advantages of an OSF dosage form (ie, rapid dissolution in the mouth, can be taken without water, and can be dosed discreetly) suggest that the sildenafil OSF may provide an attractive alternative to sildenafil citrate oral tablets.

Acute dysphonia secondary to vocal fold hemorrhage after vardenafil use.

PubMed

Singh, Vikas; Cohen, Seth M; Rousseau, Bernard; Noordzij, J Pieter; Garrett, C Gaelyn; Ossoff, Robert H

2010-06-01

Owing to their vasodilatory effects, the phosphodiesterase-5 inhibitors have become widely used for the treatment of erectile dysfunction. Among the reported adverse events of these agents are epistaxis, variceal bleeding, intracranial hemorrhage, and hemorrhoidal bleeding. We report a case of vocal fold hemorrhage that occurred after vardenafil use in a 31-year-old man who was a professional singer.

Effectiveness of Phosphodiesterase 5 Inhibitors in the Treatment of Erectile Dysfunction in Patients with Spinal Cord Trauma: Systematic Review and Meta-Analysis.

PubMed

García-Perdomo, Herney Andrés; Echeverría-García, Fernando; Tobías, Aurelio

2017-01-01

To determine the effectiveness of the Phosphodiesterase 5 (PDE5) Inhibitors for the treatment of erectile dysfunction in patients with spinal trauma. A systematic review and meta-analysis comparing PDE5 inhibitors versus placebo were carried out for clinical trials conducted between 1980 and 2014 that evaluated male patients older than 18 years, diagnosed with spinal cord trauma and erectile dysfunction. We designed a search strategy for Medline, CENTRAL, EMBASE and other electronic sources. Two investigators independently and blindly screened the studies for inclusion. A random effect meta-analysis was performed. Six studies involving 963 patients were included. Male patients over 18 years with ED attributable or subsequent to traumatic spinal cord injury (SCI) were included from these studies. In 4 of these studies, patients were randomized to the treatment group receiving sildenafil and the comparison group was placebo. Out of the remaining 2 trials, one compared tadalafil against the placebo and the other vardenafil versus placebo. The improvement on SCIs with PDE5 inhibitors was found to be large (standardized mean difference 0.71; 95% CI 0.39-1.03), with a high heterogeneity (I2 = 74.4%). PDE5 inhibitors are effective for the treatment of erectile dysfunction secondary to SCI. © 2016 S. Karger AG, Basel.

Adulteration of herbal sexual enhancers and slimmers: The wish for better sexual well-being and perfect body can be risky.

PubMed

Skalicka-Woźniak, Krystyna; Georgiev, Milen I; Orhan, Ilkay Erdogan

2017-10-01

The popularity of herbal medicines and dietary supplements is increasing all over the world due to the many side-effects assigned to synthetic drugs. Herbal remedies should be considered as safe, with no side-effects, but unfortunately, even if they are labelled as natural, large numbers of adulterants, not only with toxic heavy metals but also with undeclared synthetic substances, have been detected up to date. In this review, the most frequent instances of adulteration of herbal medicines and dietary supplements acting as sexual enhancers and slimming products are thoroughly discussed. The great success of synthetic phosphodiesterase type-5 (PDE-5) inhibitory drugs like sildenafil, vardenafil and tadalafil, used for the treatment of erectile dysfunction has made them, as well as their unapproved analogues, popular as adulterants in herbal dietary supplements. The second group among blockbuster products are herbal preparations for slimming purpose, as obesity and gaining weight are major problems worldwide. Here, sibutramine hydrochloride monohydrate, an anti-obesity drug which inhibits serotonergic and noradrenergic reuptake, seems to be the most common adulterant. Together with large numbers of its analogues, thyroid hormones, anorexigens, diuretics, stimulants, and laxative agents are also detected in most of tested diet supplements. Copyright © 2016 Elsevier Ltd. All rights reserved.

Liquid chromatography-high resolution mass spectrometry (LC-HRMS) determination of stimulants, anorectic drugs and phosphodiesterase 5 inhibitors (PDE5I) in food supplements.

PubMed

Strano-Rossi, Sabina; Odoardi, Sara; Castrignanò, Erika; Serpelloni, Giovanni; Chiarotti, Marcello

2015-03-15

The paper describes a liquid chromatography/high resolution mass spectrometry LC/HRMS method for the simultaneous identification and quantification of stimulants (ephedrines, caffeine, anorectic drugs such as phentermine, phendimetrazine, phenmetrazine, fenfluramine, benfluorex, mephentermine, fencanfamine, sibutramine) and PDE5I (sildenafil, vardenafil and tadalafil) in food supplements using a benchtop Orbitrap mass spectrometer. The mass detector, with a nominal resolving power of 100,000 (FWHM at m/z 200), operated in full scan mode in ESI positive ionization mode. Analytes were identified by retention times, accurate masses and correspondence of experimental and calculated isotopic patterns. The limits of detection (LOD) obtained varied from 1 to 25 ng g(-1) and limits of quantification (LOQ) were 50 ng g(-1) for all compounds. The method was linear for all the analytes in the ranges from 50 to 2000 ng g(-1), giving correlation coefficients>0.99. Accuracy (intended as %E) and repeatability (% CV) were always lower than 15%. The method was applied to the analysis of 36 dietary supplements, revealing the presence of ephedrine and/or pseudoephedrine in four of them, caffeine in eight of them and sildenafil in four of them. In one case, ephedrine was not reported on the label of the dietary supplement, as well as for caffeine in other two cases. A further confirmation of the analytes identity in positive samples was obtained through in-source fragmentation and comparison of the obtained fragments and their relative abundances with those from certified standards. As the acquisition mode is full scan, it would be also possible to re-process a previously acquired datafile for the investigation of untargeted analytes. Copyright © 2014 Elsevier B.V. All rights reserved.

Sildenafil-associated hepatoxicity: a review of the literature.

PubMed

Graziano, S; Montana, A; Zaami, S; Rotolo, M C; Minutillo, A; Busardò, F P; Marinelli, E

2017-03-01

Sildenafil citrate (Viagra®) is a vasoactive agent available worldwide since 1998 for the treatment of male erectile dysfunction. It is a selective phosphodiesterase type 5-enzyme inhibitor able to potentiate the downstream effects of nitric oxide on smooth muscle relaxation and vasodilation through its effects on the cyclic guanosine monophosphate (c-GMP) pathway in the erectile tissue of the penis. When sildenafil is orally administered, it is rapidly absorbed with a maximum plasma concentration achieved within 1 h and has a terminal half-life of between 3 to 6 h. The drug is extensively and rapidly metabolized by the liver, primarily by the CYP3A4 enzyme. Although the drug is well tolerated, specific adverse events have been observed, like flushing, headaches, dyspepsia, and visual disturbances. Liver toxicity related to sildenafil consumption has been considered a very rare event. However, in the last decade, some cases of sildenafil-associated hepatotoxicity have been reported. Furthermore, some hepatic intoxications have been reported after the intake of "natural" or "herbal" aphrodisiac supplements sold through Internet, sex shops, social media, and by word-of-mouth found to contain sildenafil and other phosphodiesterase type 5 (PDE-5) inhibitors. Studies investigating a possible link between sildenafil use and liver damage are limited, and the underlying mechanism responsible for hepatotoxicity is still missing. Studies in animals evidence that the hematopoietic function of the liver may have severely been affected as a result of a probable toxic effect of sildenafil. Here, the studies reporting liver toxicity by sildenafil in humans and in animals are reported and discussed.

[Efficacy and safety of vardenafil in patients with erectile dysfunction. Results of the Mexican Multicentric Study].

PubMed

Sotomayor-de-Zavaleta, Mariano; Rubio-Aurioles, Eusebio; Feria-Bernal, Guillermo; Mendoza-Valdés, Arturo; Quinzaños-Sordo, Luis Fernando; Ugarte-y-Romano, Fernando; Hurtado-Coll, Antonio; Telich-Vidal, Martín; Barreto-Fernández, Miguel Angel; Tapia-Serrano, María del Rosario; Ureta-Sánchez, Sergio Ermen; Jaspersen-Gastelum, Jorge; Pacheco-Gahbler, Carlos; Sentíes-Hernández, Ignacio R; Olguin, Jorge; Pérez-García, Javier

2004-01-01

The objective of the present study was to determine the efficacy and safety of a fixed dose of vardenafil in the treatment of patients with erectile dysfunction (ED). This was an open label, prospective and multicentric trial. After a 4-week wash out period, all patients received 20 mg of vardenafil given on demand for 12 weeks. Primary efficacy variables were the erectile function domain of the International Index of Erectile Function (IIEF), answers to questions 2 and 3 of the Sexual Encounter Profile (SEP) and the Global Assessment Question (GAQ). All adverse events were recorded and reported. 229 patients were screened. 177 received at least one dose of vardenafil and were included in the safety analysis. Mean age was 54.4 years old. Etiology of ED was organic or mixed in 77% of the patients. Erectile function domain of the IIEF changed from a basal mean score of 14.8 to 25.5 at the end of the study. 80.5% of the patients reported erections of rigidity and duration enough for satisfactory sexual intercourse and 93.3% improved their erections at the end of the study. Adverse events were mild to moderate and the most common were headache, dyspepsia, rhinitis and facial flushing. The drop out rate due to adverse events was 1.7%. This multicenter study confirms the high efficacy of this new phosphodiesterase type 5 inhibitor, vardenafil. There was a low rate of discontinuations due to adverse events and a favorable safety profile. The results of this study are similar to the results of other studies conducted in other parts of the world.

[Tadalafil combined with behavior therapy for semen collection from infertile males in whom masturbation fails].

PubMed

Tang, Wen-Hao; Jiang, Hui; Ma, Lu-Lin; Hong, Kai; Zhao, Lian-Ming; Liu, De-Feng; Mao, Jia-Ming; Yang, Yi; Zhang, Ju; Gao, Ling; Qiao, Jie

2013-05-01

To study the effect of Tadalafil combined with behavior therapy in helping obtain semen from infertile men in whom masturbation has failed. Sixty male infertile patients from whom masturbation had failed to obtain semen were equally assigned to receive Tadalafil combined with behavior therapy (combination group) or Tadalafil only (control group). All the patients took Tadalafil 20 mg orally the night before the day of semen collection by masturbation. Before this procedure, the patients of the combination group practiced masturbation 16 - 24 times at home. The average ages of the patients were (37.0 +/- 5.1) yr and (37.5 +/- 5.2) yr and their IIEF-5 scores were 16.50 +/- 1.25 and 16.90 +/- 1.09 in the combination and the control group, respectively, neither with statistically significant difference between the two groups. Semen was successfully obtained from 9 patients (30.0%) of the combination group and 1 patient (3.33%) of the control group, with statistically significant difference between the two groups (chi2 = 7.680, P < 0.01). By training the patients and establishing a conditioned response to masturbation, Tadalafil combined with behavior therapy can significantly increase the success rate of semen collection from the male infertile patients in whom masturbation fails.

ALERT: Revatio is another brand name for sildenafil.

PubMed

Koczmara, Christine; Hyland, Sylvia; Greenall, Julie

2009-01-01

In this column, the authors highlight a medication incident that occurred with Revatio (sildenafil), along with the learnings and recommendations from a previously published ISMP Canada Safety Bulletin. It is well-known to health care practitioners that use of nitroglycerin therapy is contraindicated in patients taking sildenafil (commonly known as Viagra). Many health care practitioners may be unaware that sildenafil is also marketed under the brand name Revatio for treatment of primary pulmonary hypertension or pulmonary hypertension secondary to connective tissue disease. The following incident signals the need to heighten the awareness that Revatio is a brand name for sildenafil.

Sildenafil increases cerebrovascular reactivity: a transcranial Doppler study.

PubMed

Diomedi, M; Sallustio, F; Rizzato, B; Ferrante, F; Leone, G; Spera, E; Scarfini, M; Bernardi, G

2005-09-27

The authors performed a double-blind, placebo-controlled study in 28 patients to evaluate the effects of sildenafil on cerebral hemodynamics. A significant improvement of cerebrovascular reactivity, without any modification of other variables, was recorded 1 hour after the administration of 50 mg sildenafil. Further investigations are needed to evaluate whether cerebrovascular reactivity improvement could contribute to triggering sildenafil-induced migraine.

Enhanced dissolution of sildenafil citrate as dry foam tablets.

PubMed

Sawatdee, Somchai; Atipairin, Apichart; Sae Yoon, Attawadee; Srichana, Teerapol; Changsan, Narumon

2017-01-30

Dry foam formulation technology is alternative approach to enhance dissolution of the drug. Sildenafil citrate was suspended in sodium dodecyl sulfate solution and adding a mixture of maltodextrin and mannitol as diluent to form a paste. Sildenafil citrate paste was passed through a nozzle spray bottle to obtain smooth foam. The homogeneous foam was dried in a vacuum oven and sieved to obtain dry foam granules. The granules were mixed with croscarmellose sodium, magnesium stearate and compressed into tablet. All formulations were evaluated for their physicochemical properties and dissolution profiles. All the tested excipients were compatible with sildenafil citrate by both differential scanning calorimetry (DSC) and infrared (IR) analysis. There are no X-ray diffraction (XRD) peaks representing crystals of sildenafil citrate observed form dry foam formulations. The hardness of tablets was about 5 kg, friability test <1% with a disintegration time <5 min. The sildenafil citrate dry foam tablet had higher dissolution rate in 0.1 N HCl in comparison with commercial sildenafil citrate tablet, sildenafil citrate prepared by direct compression and wet granulation method. Sildenafil citrate dry foam tablet with the high-level composition of surfactant, water and diluent showed enhanced dissolution rate than that of the lower-level composition of these excipients. This formulation was stable under accelerated conditions for at least 6 months.

Safety and efficacy of vardenafil versus sertraline in the treatment of premature ejaculation: a randomised, prospective and crossover study.

PubMed

Mathers, M J; Klotz, T; Roth, S; Lümmen, G; Sommer, F

2009-06-01

We investigated safety and efficacy of vardenafil and sertraline in premature ejaculation (PE). Seventy-two men graded their primary PE on a scale of 0-8 (0 = almost never, 8 = almost always). Intravaginal ejaculatory latency time (IELT) was measured. Patients were included if they scored their PE as 4 or greater and their IELTs were less than 1.30 min. After 6 weeks of behavioural psychosexual therapy, 49 patients still had a PE of 4 or greater and an IELT less than 1.30 min and they were randomised: 6 weeks vardenafil (10 mg) or sertraline (50 mg). After a wash-out phase for 1 week, medication was changed in a cross-over design. Initially, all 72 men with PE received behavioural therapy. Twenty-three men were satisfied with treatment and excluded. The remaining 49 men graded their PE as 5.94 +/- 1.6 and IELT was 0.59 min and patients were randomised. Four men discontinued the study. Vardenafil improved PE grading: 2.7 +/- 2.1 (P < 0.01) and IELT increased to 5.01 +/- 3.69 (P < 0.001). PE grading improved 1.92 +/- 1.32, (P < 0.01) and IELT 3.12 +/- 1.89 (P < 0.001) with sertraline. It is concluded that vardenafil and sertraline are useful agents in the pharmacological treatment of PE.

Tadalafil attenuates hypotonicity-induced Ca2+ influx via TRPV2 and TRPV4 in primary rat bladder urothelial cell cultures.

PubMed

Dong, Xiao; Nakagomi, Hiroshi; Miyamoto, Tatsuya; Ihara, Tatsuya; Kira, Satoru; Sawada, Norifumi; Mitsui, Takahiko; Takeda, Masayuki

2018-03-22

To investigate the localization of phosphodiesterase 5 (PDE5) and the molecular mechanism underlying the effect of the PDE5 inhibitor tadalafil in signal transduction in the bladder urothelium. PDE5 expression in rat bladder tissues and cultured primary rat bladder urothelial cells was evaluated using immunochemistry and western blot assays. Ca 2+ influx in cells exposed to isotonic solution, hypotonic solution, a selective transient receptor potential vanilloid 2 (TRPV2) channel agonist (cannabidiol), a selective TRPV4 channel agonist (GSK1016790A), a TRP cation channel melastatin 7 (TRPM7) channel agonist (PIP2), or a purinergic receptor agonist (ATP) in the presence or absence of 10 µM tadalafil was evaluated using calcium imaging techniques. We also evaluated stretch-induced changes in ATP concentration in the mouse bladder in the presence or absence of 100 µM tadalafil. Immunochemistry and western blot analyses demonstrated that PDE5 is abundantly expressed in the bladder urothelium and in primary rat urothelial cells. Ca 2+ influx induced by hypotonic stimulation, GSK1016790A, or cannabidiol was significantly inhibited by tadalafil, whereas ATP-induced Ca 2+ influx was unaffected by tadalafil. PIP2 did not induce Ca2+ influx. ATP release in tadalafil-pretreated bladders significantly decreased compared to control bladders. Tadalafil attenuates Ca 2+ influx via TRPV4 and TRPV2, and inhibits ATP release in the bladder urothelium. These findings indicate that tadalafil functions as an inhibitor of urothelial signal transduction. © 2018 Wiley Periodicals, Inc.

Geochemical Fate and Transport of Sildenafil in Natural Soils

NASA Astrophysics Data System (ADS)

Turner, A. E.; Vulava, V. M.

2016-12-01

In recent years, pharmaceutical drugs have become of increasing concern to the health of our environment. As a result of wastewater treatment plant discharge and various sources of surface runoff, pharmaceuticals can be found in trace amounts in our most common water resources. Sildenafil, a drug marketed to treat erectile dysfunction, is amongst the top 20 most prescribed pharmaceutical products in the U.S. Sildenafil is a complex polar organic molecule with multiple amine functional groups, which gives it acid-base functionality. The most common pKa of this molecule is approximately 6.0 and water solubility ranges from 3.5 to 4.6 mg/L. The goal of this project is to examine the sorption and transport behavior of sildenafil in natural organic matter- (OM) and clay-rich soils. Soils used for this study were collected from undisturbed forested areas in Francis Marion National Forest, Charleston, SC. A series of batch sorption isotherm and column transport experiments were conducted with these soils. Sildenafil was analyzed using high performance liquid chromatography (HPLC) and liquid chromatography mass spectrometry (LC-MS) techniques. Batch sorption isotherm experiments produced nonlinear data for both OM- and clay-rich soil types. The data shows that sildenafil sorbs more strongly to the clay-rich soils than to the OM-rich soils. This suggests that sildenafil behaved as a cation and preferentially sorbed with the negatively-charged clay minerals. The transport behavior of sildenafil as determined by experiments with soil-packed glass chromatography columns confirmed this behavior. The resulting breakthrough curves show that sildenafil is strongly retarded in clay-rich soils. Our studies do not show degradation or transformation of sildenafil in soils. The results from this study have strong implications for environmental management of pharmaceutical chemical effluents and disposal.

Tadalafil in the management of lower urinary tract symptoms: a review of the literature and current practices in Russia

PubMed Central

Govorov, Alexander; Kasyan, George; Priymak, Diana; Pushkar, Dmitry

2014-01-01

Introduction Strong epidemiologic evidence supports correlation between lower urinary tract symptoms due to benign prostatic hyperplasia (LUTS/BPH) and erectile dysfunction (ED). The link has biologic plausibility given phosphodiesterase type 5 (PDE5) expression in pelvic structures. PDE5 inhibitors target pathophysiologic processes implicated in LUTS/BPH. Material and methods This review highlights the efficacy and safety of the daily use of a PDE5 inhibitor tadalafil in LUTS/BPH, with a focus on LUTS/BPH medical management in Russia. Results Alpha–blockers and phytotherapy are major components of the current LUTS/BPH therapy in Russia. Russian regulatory authorities granted approval for once–daily tadalafil for treatment of LUTS/BPH in January 2012. In a pivotal study, tadalafil 5 mg once–daily significantly improved International Prostate Symptom Score (IPSS) over 12 weeks vs. placebo (P = .004) regardless of baseline ED severity. IPSS improvement was maintained at 12 weeks. Integrated analysis of randomized studies showed that tadalafil 5 mg once–daily resulted in significant symptom improvements across a range of men with LUTS/BPH. Relief of LUTS due to tadalafil was independent of improvement in ED; improvements in IPSS and erectile function were only weakly correlated (r = –0.229). Another pooled analysis found similar improvement in LUTS/BPH between men with or without ED, with non–significant P values for treatment–by–ED–status interactions for total IPSS ( P = .73). Non–registration studies of tadalafil and alpha–blocker co–therapy in LUTS/BPH suggest an additive effect, but co–therapy is not recommended in current tadalafil prescribing instructions. Conclusions Tadalafil results in symptom improvements across a range of men with LUTS/BPH and represents a new treatment option for patients in Russia with LUTS/BPH. PMID:25140232

Effect of tadalafil administration on insulin secretion and insulin sensitivity in obese men.

PubMed

González-Ortiz, Manuel; Martínez-Abundis, Esperanza; Hernández-Corona, Diana M; Ramírez-Rodríguez, Alejandra M

2017-10-01

To evaluate the effect of tadalafil administration on insulin secretion and insulin sensitivity in obese men without diabetes. A randomized, double-blind, placebo-controlled clinical trial was carried out in obese male patients between 30 and 50 years of age. Eighteen subjects were randomly assigned to two groups of nine patients each. During a 28-day period, subjects received 5 mg orally of tadalafil or placebo each night. Patients were evaluated before and after the intervention. Total insulin secretion and first phase of insulin secretion were calculated by insulinogenic index and Stumvoll index, respectively, and insulin sensitivity was calculated using the Matsuda index. Tolerability and compliance were evaluated permanently throughout the study. There were no significant differences after administration of tadalafil in total insulin secretion (0.82 ± 0.45 vs. 0.61 ± 0.27, p = 0.594), first phase of insulin secretion (1332 ± 487 vs. 1602 ± 800, p = 0.779) and insulin sensitivity (4.6 ± 1.2 vs. 4.9 ± 2.5, p = 0.779). No significant differences were shown in other measurements. Tadalafil administration for 28 days did not modify insulin secretion or insulin sensitivity in obese men.

Sildenafil citrate therapy for severe early-onset intrauterine growth restriction.

PubMed

von Dadelszen, P; Dwinnell, S; Magee, L A; Carleton, B C; Gruslin, A; Lee, B; Lim, K I; Liston, R M; Miller, S P; Rurak, D; Sherlock, R L; Skoll, M A; Wareing, M M; Baker, P N

2011-04-01

Sildenafil citrate therapy for severe early-onset intrauterine growth restriction. BJOG 2011;118:624-628. Currently, there is no effective therapy for severe early-onset intrauterine growth restriction (IUGR). Sildenafil citrate vasodilates the myometrial arteries isolated from women with IUGR-complicated pregnancies. Women were offered Sildenafil (25 mg three times daily until delivery) if their pregnancy was complicated by early-onset IUGR [abdominal circumference (AC)< 5th percentile] and either the gestational age was <25(+0) weeks or an estimate of the fetal weight was <600 g (excluding known fetal anomaly/syndrome and/or planned termination). Sildenafil treatment was associated with increased fetal AC growth [odds ratio, 12.9; 95% confidence interval (CI), 1.3, 126; compared with institutional Sildenafil-naive early-onset IUGR controls]. Randomised controlled trial data are required to determine whether Sildenafil improves perinatal outcomes for early-onset IUGR-complicated pregnancies. © 2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2011 RCOG.

Protective effect of tadalafil on the functional and structural changes of the rat ventral prostate caused by chronic pelvic ischemia.

PubMed

Zarifpour, Mona; Nomiya, Masanori; Sawada, Norifumi; Andersson, Karl-Erik

2015-02-15

The etiology of Benign Prostatic Hyperplasia (BPH), a common among aged men, is not fully understood, however, in addition to androgens and aging, chronic ischemia has been proposed to contribute. Using an established rat model, we investigated whether chronic ischemia alters the structural and functional properties of the ventral rat prostate, and whether phosphodiesterase type 5 (PDE5) inhibitor (tadalafil) may have a protective action. Adult male Sprague-Dawley rats were divided into control, arterial endothelial injury (AI), and AI with tadalafil treatment (AI-tadalafil) groups. AI and AI-tadalafil groups underwent endothelial injury of the iliac arteries and received a 2% cholesterol diet following AI. AI-tadalafil rats were treated with tadalafil (2 mg/kg/day) orally for 8 weeks after AI. The control group received a regular diet. After 8 weeks, animals were sacrificed, and pharmacological and morphological studies on prostate tissues were performed. Iliac arteries from AI rats displayed neo-intimal formation and luminal occlusion, an effect that was not prevented by tadalafil treatment. In the AI group, there was an obvious epithelial atrophy and a statistically significant increase in collagen fibers compared with the controls. Immunohistochemically, there was an up-regulation of smooth muscle α-actin (SMA). Contractile responses of prostate strips to KCl, electrical field stimulation (EFS), and phenylephrine (PE) were significantly higher after AI than in controls. Chronic treatment with tadalafil prevented the increase in contractile responses in ischemic tissue, and decreased the collagen deposition compared with the AI group. In this rat model, chronic pelvic ischemia caused distinct functional and morphological changes in the prostate. Prostatic tissue from ischemic animals showed an increased contractile response to electrical and pharmacological stimulation, an increase in SMA, and an increased deposition of collagen. All these changes could be

Effect of sildenafil citrate and a nitric oxide donating sildenafil derivative, NCX 911, on cavernosal relaxation and superoxide formation in hypercholesterolaemic rabbits.

PubMed

Shukla, Nilima; Jones, Robert; Persad, Raj; Angelini, Gianni D; Jeremy, Jamie Y

2005-07-11

Hypercholesterolaemia promotes erectile dysfunction through increased superoxide formation and negation of nitric oxide (NO) bioactivity in cavernosal tissue. The source of superoxide has not been clearly defined, however. Sildenafil (Viagra), the standard therapy for erectile dysfunction, may also be rendered more effective by the presence of an NO donor. One drug that intrinsically fulfils this criterion is sildenafil nitrate (NCX 911), an NO donating derivative of sildenafil. The objective of this study, therefore, was to determine the source of superoxide and its effect on erectile function in corpus cavernosum from hypercholesterolaemic rabbits and to determine whether NCX 911 confers an improvement over sildenafil citrate in this model. Hypercholesterolaemia elicited an increase in superoxide formation by rabbit cavernosal tissue and a reduction of carbachol-stimulated relaxation both of which were reversed by diphenylene iodonium chloride and apocynin (NADPH oxidase inhibitors). In response to sodium nitroprusside, hypercholesterolaemia also caused an attenuation of cavernosal relaxation which was not reversed with NADPH oxidase inhibitors. Both sildenafil citrate and NCX 911 significantly reversed impaired carbachol-stimulated relaxation and inhibited superoxide formation by cavernosal tissue from hypercholesterolaemic rabbits, NCX 911 being more potent. NCX 911 also augmented cavernosal cGMP levels, an effect blocked by the guanylyl cyclase inhibitor, 1H-{1,2,4}oxadiazolo {4,3-a}quinoxalin-1-one (ODQ). These data demonstrate that hypercholesterolaemia promotes erectile dysfunction through an augmentation of superoxide derived from NADPH oxidase in cavernosal tissue. It also indicates that NO donating sildenafil may be therapeutically more beneficial than conventional sildenafil in treating erectile dysfunction with an oxidative stress-related aetiology.

Central serous chorioretinopathy due to tadalafil use.

PubMed

Türkcü, Fatih Mehmet; Yüksel, Harun; Şahin, Alparslan; Murat, Mehmet; Bozkurt, Yaşar; Çaça, Ihsan

2013-04-01

Phosphodiesterase-5 (PDE5) inhibitors are commonly used in the treatment of erectile dysfunction. There are a small number of case reports that associate this agent with central serous chorioretinopathy (CSCR). Our report presents the treatment approach to a 42-year-old patient who described blurred vision and metamorphopsia and was diagnosed with CSCR following the use of tadalafil, a PDE5 inhibitor.

Sildenafil citrate, bronchopulmonary dysplasia and disordered pulmonary gas exchange: any benefits?

PubMed

Nyp, M; Sandritter, T; Poppinga, N; Simon, C; Truog, W E

2012-01-01

The objective of this study is to determine the effects that sildenafil citrate has on gas exchange in infants with bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH). A retrospective review was performed from 2005 to 2009. Infants treated with sildenafil citrate for greater than 48  h were included. Standard patient data was collected, including echocardiogram, inspired oxygen and systemic blood pressure, before and during administration of sildenafil citrate. Sildenafil citrate was used in 21 preterm infants with BPD-associated PH. A significant reduction in estimated right ventricular peak systolic pressure was seen after initiation of sildenafil citrate, with the majority of infants showing no improvement in gas exchange at 48  h of treatment. Four infants died during treatment. Sildenafil citrate reduced estimated pulmonary artery pressures, but this reduction was not reflected in improved gas exchange within the first 48  h.

Evaluation of the efficacy of once-daily use of tadalafil vs. on-demand use. Is there a cumulative effect?

PubMed

Jamshidian, Hasan; Borhan, Armin; Kooraki, Soheil; Borhan, Arash

2012-11-01

To assess and compare the efficacy of on-demand versus daily dosages of tadalafil in the treatment of erectile dysfunction. The case-control double-blind study was conducted at the Department of Urology, Tehran University of Medical Science, Imam Khomeini Hospital, from March 2008 to January 2010. It comprised 100 males suffering from erectile dysfunction who were randomised into two groups; one receiving on-demand tadalafil (10mg), and the other receiving once-daily dose of tadalafil (10mg). The erectile function domain of the International Index of Erectile Function was evaluated initially at the baseline and then at 24 weeks after treatment. To evaluate the possible cumulative effect of tadalafil, the index was measured in the group taking daily tadalafil at 12 weeks after the initiation of the treatment. SPSS 13 was used for statistical analysis. The study showed significant improvement in the mean erectile function domain measured after 24 weeks in both daily (17.08+/-3.896 vs baseline 12.64+/-2.92; p<0.001) and on-demand (15.46+/-3.64 vs baseline 13.48+/-2.86; p<0.001) groups. Data showed significant difference in mean scores between on-demand and daily groups (p = 0.03). In daily group, the mean domain measured at the 24th week showed significant improvement compared to the mean score of the 12th week (p <0.001). Treatment with daily tadalafil was associated with a significantly higher erectile function domain score compared to the on-demand use. The significant difference between mean scores of 12th week and 24th week in the daily group points towards the possible cumulative effect of tadalafil.

Cardiovascular effects of sildenafil citrate and recommendations for its use.

PubMed

Kloner, R A; Zusman, R M

1999-09-09

Sildenafil citrate is the first orally active therapy proved to be effective and safe treatment for erectile dysfunction (ED). Because men with cardiovascular disease are at increased risk of developing ED, and because ED and cardiovascular disease share important risk factors, attention has focused recently on the use of sildenafil in these men. When used in combination with nitroglycerin and other nitric oxide (NO) donors, sildenafil may potentiate major drops in blood pressure. Use of nitrate antianginal agents are an absolute contraindication to sildenafil use. In normotensive men and in men receiving antihypertensive medications evaluated in Phase II/III clinical trials, sildenafil use at the recommended doses (25-100 mg 1 hour before sexual intercourse and no more than once daily) was associated with modest, transient reductions in blood pressure and negligible effects on heart rate. In a more recent study, sildenafil was well tolerated in patients receiving antihypertensive medications and was not associated with major decreases in blood pressure. From the time of its approval in the United States in March 1998 through mid-November 1998, with approximately 6 million prescriptions written, 130 deaths were reported by the US Food and Drug Administration (FDA). Seventy-seven of the men who died had documented cardiovascular events. Sixteen men took or were administered nitroglycerin or an organic nitrate; 3 others had nitroglycerin in their possession. Physician prescribing guidelines issued by the American College of Cardiology/American Heart Association (ACC/AHA) recommend caution when prescribing sildenafil to men with certain cardiovascular conditions, liver or kidney disease, and to those taking medications that may prolong sildenafil's half-life (e.g., erythromycin or cimetidine). Those with known or suspected coronary artery disease may benefit from an exercise test to determine whether resumption of sexual activity with use of sildenafil is likely to be

Impact of sildenafil on survival of patients with idiopathic pulmonary arterial hypertension.

PubMed

Zeng, Wei-Jie; Sun, Yun-Juan; Gu, Qing; Xiong, Chang-Ming; Li, Jian-Jun; He, Jian-Guo

2012-09-01

It has been reported that short-term sildenafil therapy is safe and effective for patients with pulmonary arterial hypertension. However, data regarding the impact of sildenafil on the survival of patients with idiopathic pulmonary arterial hypertension remain limited. The study was conducted on 77 patients with newly diagnosed idiopathic pulmonary arterial hypertension at Fu Wai Hospital between September 2005 and September 2009. Patients were divided into 2 groups: the sildenafil group and the conventional group. Nine patients treated with sildenafil were re-evaluated by right heart catheterization after 3 months. Our data demonstrated that the 6-minute walk distance, World Health Organization functional class, mixed venous oxygen saturation, and hemodynamics significantly improved after 3 months of sildenafil therapy (P < .05). The baseline characteristics of the sildenafil group were similar to those of the conventional group. The 1-, 2-, and 3-year survival rates in the sildenafil group were 88%, 72%, and 68% compared with 61%, 36%, and 27% in the conventional group (P < .001). The absence of sildenafil therapy, lower body mass index, and lower mixed venous oxygen saturation were found to be independent predictors of mortality. In conclusion, sildenafil therapy was found to be associated with improved survival in patients with idiopathic pulmonary arterial hypertension.

Bilateral cerebral hemispheric infarction associated with sildenafil citrate (Viagra) use.

PubMed

Kim, K-K; Kim, D G; Ku, Y H; Lee, Y J; Kim, W-C; Kim, O J; Kim, H S

2008-03-01

Sildenafil citrate (Viagra) is one of the frequently prescribed drugs for men with erectile dysfunction. We describe a 52-year-old man with bilateral middle cerebral artery (MCA) territory infarction after sildenafil use. He ingested 100 mg of sildenafil and about 1 h later, he complained of chest discomfort, palpitation and dizziness followed by mental obtundation, global aphasia and left hemiparesis. Brain magnetic resonance imaging documented acute bilateral hemispheric infarction, and cerebral angiography showed occluded bilateral MCA. Despite significant bilateral MCA stenosis and cerebral infarction, systemic hypotension persisted for a day. We presume that cerebral infarction was caused by cardioembolism with sildenafil use.

Sildenafil Inhibits the Proliferation of Cultured Human Endothelial Cells

PubMed Central

Erdogan, Ali; Luedders, Doerte Wiebke; Muenz, Benedikt Manuel; Schaefer, Christian Alexander; Tillmanns, Harald; Wiecha, Johannes; Kuhlmann, Christoph Ruediger Wolfram

2007-01-01

The proliferation of endothelial cells plays a crucial role in the development of intraplaque angiogenesis (IPA). IPA is a major source of intraplaque hemorrhage and therefore contributes to the destabilization of atherosclerotic plaques. Therefore, the aim of the present study was to examine, whether sildenafil inhibits endothelial cell growth. The proliferation of human endothelial cells derived from umbilical cord veins (HUVEC) was examined on DNA level by measurements of (3H)-thymidine incorporation. Cell viability was analyzed using trypan blue staining. The proliferation of cultured human endothelial cells was significantly decreased by 1 μmol/l (-48.4%) and 10 μmol/l (-89.6%) sildenafil (n=10, p<0.05). This was not a cytotoxic effect, because cell viability was only reduced at sildenafil concentrations of 50 μmol/l or greater. In addition sildenafil significantly reduced endothelial proliferation induced by bFGF (n=10, p<0.05). The presented results demonstrate an antiangiogenic effect of sildenafil that might be useful in the prevention of atherosclerotic plaque vascularization. PMID:23675029

Sildenafil citrate monohydrate-cyclodextrin nanosuspension complexes for use in metered-dose inhalers.

PubMed

Sawatdee, Somchai; Phetmung, Hirihattaya; Srichana, Teerapol

2013-10-15

Sildenafil is a selective phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction and pulmonary hypertension. Sildenafil citrate monohydrate was complexed with α-, hydroxypropyl-β- and γ-cyclodextrin (α-CD, HP-β-CD and γ-CD, respectively) to enhance its water solubility. The complexes of sildenafil citrate monohydrate with all types of CDs were characterized by phase solubility diagrams, (1)H and (13)C NMR, and dielectric constants. Sildenafil citrate monohydrate complexed with CDs was developed as nanosuspensions for use in a pressurized metered-dose inhaler (pMDI). Sildenafil citrate monohydrate pMDI formulations were prepared by a bottom-up process using dried ethanol as a solvent and HFA-134a as an antisolvent and propellant in order to form nanosuspensions. A 3×3 factorial design was applied for the contents of the dried ethanol and HFA-134a propellant. The phase solubility profiles of the sildenafil and cyclodextrins were described as AL type with a mole ratio 1:1. The piperazine moiety of sildenafil formed an inclusion in the cavity of the CDs. The particle diameters of the sildenafil citrate monohydrate suspensions in pMDIs were all within a nanosuspension size range. An assay of the sildenafil content showed that the formation of complexes with CDs was close to 100%. In the case of the formulations with CDs, the emitted doses varied within 97.4±10.8%, the fine particle fractions (FPFs) were in a range of 45-81%, the fine particle dose (FPD) was 12.6±2.0 μg and the mass median aerodynamic diameters (MMADs) were 1.86±0.41 μm. In contrast, the formulations without CDs produced a low emitted dose of sildenafil (<60%). Therefore, only sildenafil citrate monohydrate pMDI formulations containing CDs were suitable for use as aerosols. Copyright © 2013 Elsevier B.V. All rights reserved.

Sildenafil vaginal suppositories: preparation, characterization, in vitro and in vivo evaluation.

PubMed

Shanmugam, Srinivasan; Kim, Young-Hun; Park, Jeong-Hee; Im, Ho Taek; Sohn, Young Taek; Kim, Kyeong Soo; Kim, Yong-Il; Yong, Chul Soon; Kim, Jong Oh; Choi, Han-Gon; Woo, Jong Soo

2014-06-01

The main objective was to investigate the in vitro release profile/kinetics, and in vivo plasma pharmacokinetics (PK) and organ biodistribution (BD) of the prepared sildenafil vaginal suppositories (SVS). Suppositories containing 25 mg of sildenafil were prepared by the cream melting technique using Witepsol H-15 as a suppository base. The suppositories were characterized for weight variation, content uniformity, hardness, disintegration time and crystallinity change. The in vitro dissolution in pH 4.5, and in vivo plasma PK and organ BD of sildenafil from SVS in female Sprague Dawley rats, were also investigated. The mean weight variation, content uniformity, hardness and disintegration time of the prepared SVS were 1.127 ± 0.020 g, 98.25 ± 2.50%, 2.5 ± 0.08 kg and 9 ± 1.0 min, respectively. The release of sildenafil from the SVS was more than 90% at 30 min, with a release kinetic of Hixson--Crowell model and non-Fickian diffusion (n = 0.464). The plasma PK study demonstrated a significantly lower Cmax (∼10 times) and AUC0-24 h (∼13 times) of sildenafil in plasma following intravaginal (IVG) administration of suppositories compared to oral (PO) administration of sildenafil solution. Nevertheless, the organ BD study showed a phenomenally higher Cmax (∼40 times) and AUC0-24 h (∼20 times) of sildenafil in uterus following IVG administration of suppositories than PO administration of sildenafil solution. This study demonstrated enhanced sildenafil exposure in the uterus following IVG administration of SVS, which could be used to target the uterus for therapeutic benefits.

Sildenafil restores endothelial function in the apolipoprotein E knockout mouse

PubMed Central

2013-01-01

Background Atherosclerosis is an inflammatory process of the arterial walls and is initiated by endothelial dysfunction accompanied by an imbalance in the production of reactive oxygen species (ROS) and nitric oxide (NO). Sildenafil, a selective phosphodiesterase-5 (PDE5) inhibitor used for erectile dysfunction, exerts its cardiovascular effects by enhancing the effects of NO. The aim of this study was to investigate the influence of sildenafil on endothelial function and atherosclerosis progression in apolipoprotein E knockout (apoE−/−) mice. Methods ApoE−/− mice treated with sildenafil (Viagra®, 40 mg/kg/day, for 3 weeks, by oral gavage) were compared to the untreated apoE−/− and the wild-type (WT) mice. Aortic rings were used to evaluate the relaxation responses to acetylcholine (ACh) in all of the groups. In a separate set of experiments, the roles of NO and ROS in the relaxation response to ACh were evaluated by incubating the aortic rings with L-NAME (NO synthase inhibitor) or apocynin (NADPH oxidase inhibitor). In addition, the atherosclerotic lesions were quantified and superoxide production was assessed. Results Sildenafil restored the vasodilator response to acetylcholine (ACh) in the aortic rings of the apoE−/− mice. Treatment with L-NAME abolished the vasodilator responses to ACh in all three groups of mice and revealed an augmented participation of NO in the endothelium-dependent vasodilation in the sildenafil-treated animals. The normalized endothelial function in sildenafil-treated apoE−/− mice was unaffected by apocynin highlighting the low levels of ROS production in these animals. Moreover, morphological analysis showed that sildenafil treatment caused approximately a 40% decrease in plaque deposition in the aorta. Conclusion This is the first study demonstrating the beneficial effects of chronic treatment with sildenafil on endothelial dysfunction and atherosclerosis in a model of spontaneous hypercholesterolemia. These data

Effects of tadalafil administration on plasma markers of exercise-induced muscle damage, IL6 and antioxidant status capacity.

PubMed

Ceci, Roberta; Duranti, Guglielmo; Sgrò, Paolo; Sansone, Massimiliano; Guidetti, Laura; Baldari, Carlo; Sabatini, Stefania; Di Luigi, Luigi

2015-03-01

Physical exercise is associated with enhanced production of reactive oxygen species, which if uncontrolled can result in tissue injury. Phosphodiesterase type 5 inhibitors (PDE5i) exhibit protective effect against oxidative stress, both in animals and healthy/unhealthy humans. However, the effect of a chronic administration of PDE5i, particularly combined with physical exercise, has never been investigated. The present study was designed to evaluate the effect of the long-acting PDE5i tadalafil on oxidative status and muscle damage after exhaustive exercise in healthy males included in a double-blind crossover trial. Tadalafil, having a putative antioxidant activity, may reduce oxidative damage after strenuous exercise. Each volunteer randomly received two tablets of placebo or tadalafil (20 mg/day) with 36 h of interval before performing exhaustive exercise. After 2 weeks of washout, the volunteers were crossed over. Blood samples were collected immediately before exercise, immediately after, and during recovery (15, 30, 60 min). Plasma total antioxidant status, glutathione homeostasis (GSH/GSSG), malondialdehyde (MDA), protein carbonyls, creatine kinase (CK), lactate dehydrogenase (LDH) and the inflammatory cytokine interleukin 6 were assessed. Tadalafil administration per se affected redox homeostasis (GSH/GSSG -36%; p < 0.05), cellular (CK +75% and LDH +36%; p < 0.05) and oxidative damage (MDA +41% and protein carbonyls +50%; p < 0.05) markers. The exhaustive exercise increased all the above-reported biochemical parameters, with subjects from the tadalafil group showing significantly higher values with respect to the placebo group. A prolonged exposure to tadalafil decreases antioxidant capacity at resting condition, therefore making subjects more susceptible to the oxidative stress induced by an exhaustive bout of exercise.

Effects and mechanisms of action of sildenafil citrate in human chorionic arteries

PubMed Central

Maharaj, Chrisen H; O'Toole, Daniel; Lynch, Tadhg; Carney, John; Jarman, James; Higgins, Brendan D; Morrison, John J; Laffey, John G

2009-01-01

Objectives Sildenafil citrate, a specific phosphodiesterase-5 inhibitor, is increasingly used for pulmonary hypertension in pregnancy. Sildenafil is also emerging as a potential candidate for the treatment of intra-uterine growth retardation and for premature labor. Its effects in the feto-placental circulation are not known. Our objectives were to determine whether phosphodiesterase-5 is present in the human feto-placental circulation, and to characterize the effects and mechanisms of action of sildenafil citrate in this circulation. Study Design Ex vivo human chorionic plate arterial rings were used in all experiments. The presence of phosphodiesterase-5 in the feto-placental circulation was determined by western blotting and immunohistochemical staining. In a subsequent series of pharmacologic studies, the effects of sildenafil citrate in pre-constricted chorionic plate arterial rings were determined. Additional studies examined the role of cGMP and nitric oxide in mediating the effects of sildenafil. Results Phosphodiesterase-5 mRNA and protein was demonstrated in human chorionic plate arteries. Immunohistochemistry demonstrated phosphodiesterase-5 within the arterial muscle layer. Sildenafil citrate produced dose dependent vasodilatation at concentrations at and greater than 10 nM. Both the direct cGMP inhibitor methylene blue and the cGMP-dependent protein kinase inhibitor Rp-8-Br-PET-cGMPS significantly attenuated the vasodilation produced by sildenafil citrate. Inhibition of NO production with L-NAME did not attenuate the vasodilator effects of sildenafil. In contrast, sildenafil citrate significantly enhanced the vasodilation produced by the NO donor sodium nitroprusside. Conclusion Phosphodiesterase-5 is present in the feto-placental circulation. Sildenafil citrate vasodilates the feto-placental circulation via a cGMP dependent mechanism involving increased responsiveness to NO. PMID:19389232

Sildenafil exposure and hemodynamic effect after stage II single-ventricle surgery

PubMed Central

Hill, Kevin D.; Tunks, Robert D.; Barker, Piers C. A.; Benjamin, Daniel K.; Cohen-Wolkowiez, Michael; Fleming, Gregory A.; Laughon, Matthew; Li, Jennifer S.

2013-01-01

Objective To determine sildenafil exposure and hemodynamic effect in children after stage II single-ventricle surgery. Design Prospective, dose escalation trial. Setting Single-center, pediatric catheterization laboratory. Patients 12 children post stage II single-ventricle surgical palliation and undergoing elective cardiac catheterization: median age 1.9 years (range: 0.8, 4.0), weight 11 kg (8, 13), 9 females, and 10 with a single right ventricle. Interventions Catheterization and echocardiography performed before and immediately after single-dose intravenous sildenafil (0.125, 0.25, 0.35, or 0.45 mg/kg over 20 minutes). Measurements Peak sildenafil and des-methyl sildenafil concentration, change in hemodynamic parameters measured by cardiac catheterization and echocardiography including indexed pulmonary vascular resistance, and myocardial performance. Main Results Maximum sildenafil concentrations ranged from 92–775 ng/ml and were above the in vitro threshold needed for 77% phosphodiesterase type-5 (PDE-5) inhibition in 80% of subjects and 90% inhibition in 80% of subjects with doses ≥0.35 mg/kg. Sildenafil lowered pulmonary vascular resistance index (PVRI) in all 12 subjects (median PVRI 2.2 [range: 1.6, 7.9]; decreased to 1.7 [1.2, 5.4] WU x m2; p<0.01) with no dose-response effect. Sildenafil improved pulmonary blood flow (+8% [0, 20], p=0.04) and saturations (+2% [0, 16], p=0.04) in those with baseline PVRI ≥2 WU x m2 (n=7). Change in saturations correlated inversely with change in PVRI (r2 = 0.74 p<0.01). Sildenafil also lowered mean blood pressure (−12% [−20, +10]; p=0.04). There was no change in cardiac index and no effect on myocardial performance. There were no adverse events. Conclusions Sildenafil demonstrated non-linear exposure with high inter-individual variability but was well tolerated and effectively lowered PVRI in all subjects. Sildenafil did not acutely improve myocardial performance or increase cardiac index. PMID:23823195

Sildenafil Stimulates Aqueous Humor Turnover in Rabbits

PubMed Central

Alvarez, Lawrence J.; Zamudio, Aldo C.; Candia, Oscar A.

2013-01-01

Sildenafil citrate increases ocular blood flow and accelerates the rate of anterior chamber refilling after paracentesis. The latter effect could have resulted from a reduction in outflow facility or from an increase in aqueous humor (AH) production. In this study, we used scanning ocular fluorophotometry to examine the effects of sildenafil on AH turnover, and thus, AH production in eyes of live normal rabbits. For this, the rate of aqueous humor flow (AHF) was quantified with a commercially available fluorophotometer that measured the rate of fluorescein clearance from the anterior segment, which predominantly occurs via the trabecular meshwork. After ≈ 2 hrs of control scans to determine the baseline rate of AHF, the rabbits were fed 33 mg of sildenafil and allowed ≈ 45 min for the drug to enter the systemic circulation. Thereafter, fluorescence scans were retaken for an additional 90–120 min. Sildenafil ingestion increased AHF by about 36%, from 2.31 μL/min to 3.14 μL/min (P< 0.001, as two-tailed paired data, n= 20 eyes). This observation indicates that sildenafil citrate, which is a phosphodiesterase type-5 inhibitor currently marketed as a vasodilator (e.g., Viagra, Revatio), stimulates AHF in rabbits. Our results seem consistent with reports indicating that the drug dilates intraocular arteries and augments intraocular vascular flow. These physiological responses to the agent apparently led to increased fluid entry into the anterior chamber. As such, the drug might have utility in patients with ocular hypotony resulting from insufficient AH formation. PMID:23562660

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic-Banded Mini-Swine.

PubMed

Hiemstra, Jessica A; Lee, Dong I; Chakir, Khalid; Gutiérrez-Aguilar, Manuel; Marshall, Kurt D; Zgoda, Pamela J; Cruz Rivera, Noelany; Dozier, Daniel G; Ferguson, Brian S; Heublein, Denise M; Burnett, John C; Scherf, Carolin; Ivey, Jan R; Minervini, Gianmaria; McDonald, Kerry S; Baines, Christopher P; Krenz, Maike; Domeier, Timothy L; Emter, Craig A

2016-04-20

Cyclic guanosine monophosphate-protein kinase G-phosphodiesterase 5 signaling may be disturbed in heart failure (HF) with preserved ejection fraction, contributing to cardiac remodeling and dysfunction. The purpose of this study was to manipulate cyclic guanosine monophosphate signaling using the dipeptidyl-peptidase 4 inhibitor saxagliptin and phosphodiesterase 5 inhibitor tadalafil. We hypothesized that preservation of cyclic guanosine monophosphate cGMP signaling would attenuate pathological cardiac remodeling and improve left ventricular (LV) function. We assessed LV hypertrophy and function at the organ and cellular level in aortic-banded pigs. Concentric hypertrophy was equal in all groups, but LV collagen deposition was increased in only HF animals. Prevention of fibrotic remodeling by saxagliptin and tadalafil was correlated with neuropeptide Y plasma levels. Saxagliptin better preserved integrated LV systolic and diastolic function by maintaining normal LV chamber volumes and contractility (end-systolic pressure-volume relationship, preload recruitable SW) while preventing changes to early/late diastolic longitudinal strain rate. Function was similar to the HF group in tadalafil-treated animals including increased LV contractility, reduced chamber volume, and decreased longitudinal, circumferential, and radial mechanics. Saxagliptin and tadalafil prevented a negative cardiomyocyte shortening-frequency relationship observed in HF animals. Saxagliptin increased phosphodiesterase 5 activity while tadalafil increased cyclic guanosine monophosphate levels; however, neither drug increased downstream PKG activity. Early mitochondrial dysfunction, evident as decreased calcium-retention capacity and Complex II-dependent respiratory control, was present in both HF and tadalafil-treated animals. Both saxagliptin and tadalafil prevented increased LV collagen deposition in a manner related to the attenuation of increased plasma neuropeptide Y levels. Saxagliptin

Evaluating the safety of intermittent intravenous sildenafil in infants with pulmonary hypertension.

PubMed

Darland, Leanna K; Dinh, Kimberly L; Kim, Shelly; Placencia, Jennifer L; Varghese, Nidhy P; Ruiz, Fadel; Mallory, George B; Fernandes, Caraciolo J

2017-02-01

To compare the occurrence of hypotension following administration of intermittent intravenous (IV) and enteral sildenafil for treatment of pulmonary hypertension (PH) in infants. We hypothesized there may be more adverse effects associated with intermittent IV sildenafil compared with enteral sildenafil. This was a retrospective matched-cohort study conducted in a tertiary care children's hospital. Patients were included if they were less than 1 year of age and received intermittent sildenafil for PH. Exclusion criteria consisted of concurrent extracorporeal membrane oxygenation during the initiation of sildenafil, the utilization of sildenafil as a one-time dose, continuation of home-dosing regimen, or inclusion in the other cohort. A total of 40 patients were matched 1:1 based on postmenstrual age and primary diagnosis. There was no statistically significant difference in the primary outcome, as 30% (6/20) of patients receiving IV sildenafil required a hypotension intervention compared with 10% (2/20) in the enteral cohort (P = 0.24). The majority of interventions occurred within 24 hr of the initiation of sildenafil with 4/6 patients (67%) in the IV group and 2/2 patients (100%) in the enteral group, respectively. Baseline mean arterial pressure was significantly lower in the IV patients that required an intervention compared with those that did not (44 ± 6.3 vs. 65 ± 13.4 mmHg, P = 0.0024). There were no statistically significant differences in safety outcomes between intermittent IV and enteral sildenafil in infants with PH. Hemodynamic parameters should be monitored closely upon sildenafil initiation. Limitations include the retrospective nature and small sample size. Pediatr Pulmonol. 2017;52:232-237. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Sildenafil citrate and sildenafil nitrate (NCX 911) are potent inhibitors of superoxide formation and gp91phox expression in porcine pulmonary artery endothelial cells.

PubMed

Muzaffar, Saima; Shukla, Nilima; Srivastava, Amit; Angelini, Gianni D; Jeremy, Jamie Y

2005-09-01

Acute respiratory distress syndrome (ARDS) is associated with increased superoxide (O(2)(*-)) formation in the pulmonary vasculature and negation of the bioavailability of nitric oxide (NO). Since NO inhibits NADPH oxidase expression through a cyclic GMP-mediated mechanism, sildenafil, a type V phosphodiesterase inhibitor, may be therapeutically effective in ARDS through an augmentation of NO-mediated inhibition of NADPH oxidase. Therefore, the effect of sildenafil citrate and NO-donating sildenafil (NCX 911) on O(2)(*-) formation and gp91(phox) (active catalytic subunit of NADPH oxidase) expression was investigated in cultured porcine pulmonary artery endothelial cells (PAECs). PAECs were incubated with 10 nM TXA(2) analogue, 9,11-dideoxy-9alpha,11alpha-methanoepoxy-prostaglandin F(2alpha) (U46619) (+/-sildenafil or NCX 911), for 16 h and O(2)(*-) formation measured spectrophometrically and gp91(phox) using Western blotting. The role of the NO-cGMP axis was studied using morpholinosydnonimine hydrochloride (SIN-1), the diethylamine/NO complex (DETA-NONOate), the guanylyl cyclase inhibitor, 1H-{1,2,4}oxadiazolo{4,3-a}quinoxalin-1-one (ODQ), and the protein kinase G inhibitor, 8-bromoguanosine-3',5'-cyclic monophosphorothioate, Rp-isomer (Rp-8-Br-cGMPS). NO release was studied using a fluorescence assay and O(2)(*-)-NO interactions by measuring nitrites. After a 16-h incubation with 10 nM U46619, both NCX 911 and sildenafil elicited a concentration-dependent inhibition of O(2)(*-) formation and gp91(phox) expression, NCX 911 being more potent (IC(50); 0.26 nM) than sildenafil citrate (IC(50); 1.85 nM). These inhibitory effects were reversed by 1 microM ODQ and 10 microM Rp-8-Br-cGMPS. NCX 911 stimulated the formation of cGMP in PAECs and generated NO in a cell-free system to a greater degree than sildenafil citrate. The inhibitory effect of sildenafil was augmented by 1 muM SIN-1 and blocked partially by the eNOS inhibitor 10 microM N(5)-(1-iminoethyl)-ornithine (L

Sildenafil for the Treatment of Congenital Nephrogenic Diabetes Insipidus.

PubMed

Assadi, Farahnak; Sharbaf, Fatemeh Ghane

2015-01-01

Congenital nephrogenic diabetes insipidus (NDI) is characterized by massive polyuria and polydipsia due to defects in the vasopressin-sensitive signaling system expression of the acuaporin-2 (AQP2) water channel of the kidney collecting duct principal cells. Current conventional treatment regimen including hydration, diuretics and nonsteroidal anti-inflammatory drugs can only partially reduce polyuria. Recent experimental studies have suggested that treatment with sildenafil, a selective phosphodiesterase inhibitor, may enhance cyclic guanosine monophosphate (cGMP)-mediated apical trafficking of AQP2 and may be effective in increasing water reabsorption in patients with congenital NDI. A 4-year old boy with X-linked NDI resistant to conventional therapy was treated with sildenafil for 10 days after a 2-day washout period between the 2 treatment regimens. Aliquots of the 24-hour urine collections before and after treatment were analyzed for urine volume, osmolality, cGMP and AQP2 determinations. Blood samples were also obtained for sodium and osmolality measurements. The primary endpoint was 24-hour urine volume after 10 days of sildenafil and conventional treatments. Compared to conventional therapy, treatment with sildenafil resulted in substantial reduction in 24-hour urine volume (1,764 vs. 950 ml) and serum sodium (148 vs. 139) mEq/l, and increased urine osmolality (104 vs. 215 mOsm/l), and AQP2 excretion (5 vs. 26 fmol/mg creatinine). The patient tolerated sildenafil well and experienced no adverse effects. Sildenafil citrate should be considered an alternative agent in the treatment of X-linked NDI resistant to conventional therapy. © 2015 S. Karger AG, Basel

Exercise Training Plus Sildenafil Treatment: Role on Autonomic and Inflammatory Markers.

PubMed

Leoni, Luis Antonio B; Fukushima, Andre R; Rocha, Leandro Y; Feriani, Daniele J; Júnior, Hélio José Coelho; Gambassi, Bruno B; Mostarda, Cristiano T; Maifrino, Laura Beatriz Mesiano; Rodrigues, Bruno

2018-06-25

The current study aimed to determine the effects of sildenafil-associated aerobic exercise training (ET) on the physical performance, hemodynamic, autonomic and inflammatory parameters of rats. Male Wistar rats were randomly assigned to: sedentary rats placebo-treated (SP); sedentary rats sildenafil-treated (SS); trained rats placebo-treated (TP); and trained rats sildenafil-treated (TS). Sildenafil treatment consisted of 8 weeks of daily oral gavage (1.5 mg/kg), one hour before the session of ET (60-75% of maximal running speed, 5 days/week, for 8 weeks). After ET period, physical capacity, hemodynamic, autonomic and skeletal muscle inflammatory profile were assessed. Chronic sildenafil treatment causes an additional increase of physical capacity in aerobically trained rats. However, these beneficial effects were accompanied by unwanted alterations, as increased of arterial pressure and peripheral sympathetic modulation, as well as exacerbated inflammatory status on skeletal muscle of rats. Taken together, these data suggest the positive and negative effects of sildenafil chronic administration, associated to aerobic ET, at doses used in clinical practice. This report stresses the importance of paying greater attention to the indiscriminate use of this substance in high-performance sports. © Georg Thieme Verlag KG Stuttgart · New York.

Protective effect of exercise and sildenafil on acute stress and cognitive function.

PubMed

Ozbeyli, Dilek; Gokalp, Ayse Gizem; Koral, Tolga; Ocal, Onur Yuksel; Dogan, Berkay; Akakin, Dilek; Yuksel, Meral; Kasimay, Ozgur

2015-11-01

There are contradictory results about the effects of exercise and sildenafil on cognitive functions. To investigate the effects of sildenafil pretreatment and chronic exercise on anxiety and cognitive functions. Wistar rats (n=42) were divided as sedentary and exercise groups. A moderate-intensity swimming exercise was performed for 6 weeks, 5 days/week, 1h/day. Some of the rats were administered orogastrically with sildenafil (25mg/kg/day) either acutely or chronically. Exposure to cat odor was used for induction of stress. The level of anxiety was evaluated by elevated plus maze test, while object recognition test was used to determine cognitive functions. Brain tissues were removed for the measurement of myeloperoxidase (MPO), malondialdehyde (MDA), nitric oxide levels, lucigenin-enhanced chemiluminescence, and for histological analysis. Increased MPO and MDA levels in sedentary-stressed rats were decreased with sildenafil applications. Chronic exercise inhibited the increase in MPO levels. Increased nitric oxide and lucigenin chemiluminescence levels in sedentary-stressed rats, were diminished with chronic sildenafil pretreatment. The time spent in the open arms of the plus maze was declined in sedentary-stressed rats, while chronic sildenafil pretreatment increased the time back to that in non-stressed rats. Acute sildenafil application to exercised rats prolonged the time spent in open arms as compared to non-treated exercise group. The time spent with the novel object, which was decreased in sedentary-stressed rats, was increased with sildenafil pretreatment. Our results suggest that sildenafil pretreatment or exercise exerts a protective effect against acute stress and improves cognitive functions by decreasing oxidative damage. Copyright © 2015 Elsevier Inc. All rights reserved.

Biowaiver or Bioequivalence: Ambiguity in Sildenafil Citrate BCS Classification.

PubMed

Miranda, Claudia; Pérez-Rodríguez, Zenia; Hernández-Armengol, Rosario; Quiñones-García, Yaidel; Betancourt-Purón, Tania; Cabrera-Pérez, Miguel Ángel

2018-05-01

The aim of the present study is to contribute to the scientific characterization of sildenafil citrate according to the Biopharmaceutics Classification System, following the World Health Organization (WHO) guidelines for biowaivers. The solubility and intestinal permeability data of sildenafil citrate were collected from literature; however, the experimental solubility studies are inconclusive and its "high permeability" suggests an API in the borderline of BCS Class I and Class II. The pH-solubility profile was determined using the saturation shake-flask method over the pH range of 1.2-6.8 at a temperature of 37 °C in aqueous media. The intestinal permeability was determined in rat by a closed-loop in situ perfusion method (the Doluisio technique). The solubility of sildenafil citrate is pH-dependent and at pH 6.8 the dose/solubility ratio obtained does not meet the WHO criteria for "high solubility." The high permeability values obtained by in situ intestinal perfusion in rat reinforce the published permeability data for sildenafil citrate. The experimental results obtained and the data available in the literature suggest that sildenafil citrate is clearly a Class II of BCS, according to the current biopharmaceutics classification system and WHO guidance.

Sildenafil citrate and uteroplacental perfusion in fetal growth restriction

PubMed Central

Dastjerdi, Marzieh Vahid; Hosseini, Sayedehafagh; Bayani, Leila

2012-01-01

Background: To determine whether the phosphodiesterase type 5 inhibitor, Sildenafil citrate, affects uteroplacental perfusion. Materials and Methods: Based on a randomized double-blinded and placebo-controlled trial, forty one pregnant women with documented intrauterine growth retardation at 24-37 weeks of gestation were evaluated for the effect of a single dose of Sildenafil citrate on uteroplacental circulation as determined by Doppler ultrasound study of the umbilical and middle cerebral arteries. Statistical analysis included χ2-test to compare proportions, and independent-samples t-test and paired student's t-test to compare continuous variables. Results: Sildenafil group fetuses demonstrated a significant decrease in systolic/diastolic ratios (0.60 [SD 0.40] [95% Cl 0.37-0.84], P=0.000), and pulsatility index (0.12 [SD 0.15] [95% Cl 0.02-0.22], P=0.019) for the umbilical artery and a significant increase in middle cerebral artery pulsatility index (MCA PI) (0.51 [SD 0.60] [95% Cl 0.16-0.85], P=0.008). Conclusion: Doppler velocimetry index values reflect decreased placental bed vascular resistance after Sildenafil. Sildenafil citrate can improve fetoplacental perfusion in pregnancies complicated by intrauterine growth restriction. It could be a potential therapeutic strategy to improve uteroplacental blood flow in pregnancies with fetal growth restriction (FGR). PMID:23798922

Sildenafil citrate (Viagra) enhances vasodilatation in fetal growth restriction.

PubMed

Wareing, Mark; Myers, Jenny E; O'Hara, Maureen; Baker, Philip N

2005-05-01

Fetal growth restriction (FGR) affects up to 8% of all pregnancies and has massive short-term (increased fetal morbidity and mortality) and long-term (increased incidence of cardiovascular disease in adulthood) health implications. Doppler waveform analysis of pregnancies complicated by FGR suggests compromised uteroplacental circulation and placental hypoperfusion. Our aim was to determine whether myometrial small artery function was aberrant in FGR and to assess whether sildenafil citrate could improve vasodilatation in FGR pregnancies. Small arteries dissected from myometrial biopsies obtained at cesarean section from normal pregnant women (n = 27) or women whose pregnancies were complicated by FGR (n = 12) were mounted on wire myographs. Vessels were constricted (with arginine vasopressin or U46619) and relaxed (with bradykinin) before and after incubation with a phosphodiesterase-5 inhibitor, sildenafil citrate. We demonstrated increased myometrial small artery vasoconstriction and decreased endothelium-dependent vasodilatation in vessels from women whose pregnancies were complicated by FGR. Sildenafil citrate significantly reduced vasoconstriction and significantly improved relaxation of FGR small arteries. We conclude that sildenafil citrate improves endothelial function of myometrial vessels from women whose pregnancies are complicated by intrauterine growth restriction. Sildenafil citrate may offer a potential therapeutic strategy to improve uteroplacental blood flow in FGR pregnancies.

Pharmacokinetics and Tolerability of Oral Sildenafil in Adults with Cystic Fibrosis Lung Disease

PubMed Central

Taylor-Cousar, JL; Wiley, C; Felton, LA; St Clair, C; Jones, M; Curran-Everett, D; Poch, K; Nichols, DP; Solomon, GM; Saavedra, MT; Accurso, FJ; Nick, JA

2014-01-01

Rationale Airway inflammation is central to cystic fibrosis (CF) pathophysiology. Pre-clinical models have shown that phosphodiesterase inhibitors (PDEi) like sildenafil have anti-inflammatory activity. PDEi have not been studied in CF subjects. Objectives We evaluated the pharmacokinetics, tolerability, and safety of sildenafil in subjects with CF. Sputum biomarkers were used to explore efficacy. Methods An open-label pilot study of oral sildenafil administration was conducted in adults with mild to moderate CF lung disease. Subjects received oral sildenafil 20 or 40 mg p.o. t.i.d. for 6 weeks. Measurements and Main Results Twenty subjects completed the study. Estimated elimination rate constants were statistically different in subjects with CF compared to previously published non-CF subjects. Side effects were generally mild. There were no drug-related serious adverse events. Sputum neutrophil elastase activity decreased. Conclusions Subjects with CF may eliminate sildenafil at a faster rate than non-CF subjects. Sildenafil administration was safe in subjects with CF, and decreased sputum elastase activity. Sildenafil warrants further study as an anti-inflammatory in CF. PMID:25466700

Sildenafil and the Internet.

PubMed

Kahan, S E; Seftel, A D; Resnick, M I

2000-03-01

The Internet is changing the way medicine is being practiced and challenging our notions of the doctor-patient relationship. We analyze the development of online prescriptions and propose guidelines for the sale of sildenafil over the Internet. Using MEDLINE, Medscape and Lexis-Nexis search engines we reviewed pertinent materials from January 1996 to July 1999 focusing on the keywords Viagra, prescription and Internet. The review included press releases, law review articles, case law, medical literature, pending litigation, proposed legislation, and federal and state statutes. Online prescriptions are an outgrowth of the mail order drug business. This development continues the historic innovations in communications and transportation that have enabled physicians to practice medicine over long distances while maintaining ties to hospitals and other specialists. While the sale of sildenafil over the Internet may be profitable and convenient, it raises a variety of legal, ethical and safety concerns. Many federal and state organizations have addressed the issue without establishing a clear standard. A clear distinction exists between online prescriptions and pharmacies. While it may be acceptable for sildenafil to be sold over the Internet given current technologies, it must be done within the confines of a traditional doctor-patient relationship. Online prescriptions must be limited to patients who live in states in which the prescribing physician is licensed. Failure to establish a doctor patient relationship in this context breeches ethical standards, and may give rise to potential civil and criminal liabilities.

Childhood sexual abuse, selective attention for sexual cues and the effects of testosterone with or without vardenafil on physiological sexual arousal in women with sexual dysfunction: a pilot study.

PubMed

van der Made, Flip; Bloemers, Jos; van Ham, Diana; El Yassem, Wadi; Kleiverda, Gunilla; Everaerd, Walter; Olivier, Berend; Tuiten, Adriaan

2009-02-01

Female sexual dysfunction (FSD) may be associated with reduced central sensitivity for sexual cues. A single dose of testosterone might induce an increase in sensitivity for sexual stimuli, which in turn allows a PDE5 inhibitor to be effective in boosting the physiological sexual response. Negative sexual experience-like childhood sexual abuse (CSA)-might be an important intervening factor in these drugs-induced alterations. To investigate if the combination of testosterone and vardenafil causes an increase in sensitivity for sexual cues and an increase in physiological sexual responding in women suffering from hypoactive sexual desire disorder (HSDD). Thirteen women with HSDD underwent four different drug treatments: (i) placebo; (ii) vardenafil; (iii) testosterone; and (iv) combination of testosterone and vardenafil. During each treatment, they performed an emotional Stroop task and watched neutral and erotic film clips. A masked version of the emotional Stroop task, and the vaginal pulse amplitude (VPA). We found different effects in women who had reported CSA (N = 5) compared with those who had not (N = 8). In women without CSA, testosterone induced an increase in their originally low levels of preconscious attention for sexual cues, while women with CSA showed a decrease in their originally high levels of attention. In these groups, we also found different effects of the combination of testosterone and vardenafil on the VPA: women without CSA revealed a statistically significant increase in their VPA during treatment with the combination of testosterone and vardenafil as compared with placebo. Women with CSA, however, showed no alterations in their physiological sexual responding during this combined drug treatment. In women without CSA, testosterone appears to activate central sexual mechanisms resulting in higher VPA under the combination of testosterone and vardenafil. This effect did not occur in women with CSA.

Sildenafil citrate and sildenafil nitrate (NCX 911) are potent inhibitors of superoxide formation and gp91phox expression in porcine pulmonary artery endothelial cells

PubMed Central

Muzaffar, Saima; Shukla, Nilima; Srivastava, Amit; Angelini, Gianni D; Jeremy, Jamie Y

2005-01-01

Acute respiratory distress syndrome (ARDS) is associated with increased superoxide (O2•−) formation in the pulmonary vasculature and negation of the bioavailability of nitric oxide (NO). Since NO inhibits NADPH oxidase expression through a cyclic GMP-mediated mechanism, sildenafil, a type V phosphodiesterase inhibitor, may be therapeutically effective in ARDS through an augmentation of NO-mediated inhibition of NADPH oxidase. Therefore, the effect of sildenafil citrate and NO-donating sildenafil (NCX 911) on O2•− formation and gp91phox (active catalytic subunit of NADPH oxidase) expression was investigated in cultured porcine pulmonary artery endothelial cells (PAECs). PAECs were incubated with 10 nM TXA2 analogue, 9,11-dideoxy-9α,11α-methanoepoxy-prostaglandin F2α (U46619) (±sildenafil or NCX 911), for 16 h and O2•− formation measured spectrophometrically and gp91phox using Western blotting. The role of the NO-cGMP axis was studied using morpholinosydnonimine hydrochloride (SIN-1), the diethylamine/NO complex (DETA-NONOate), the guanylyl cyclase inhibitor, 1H-{1,2,4}oxadiazolo{4,3-a}quinoxalin-1-one (ODQ), and the protein kinase G inhibitor, 8-bromoguanosine-3′,5′-cyclic monophosphorothioate, Rp-isomer (Rp-8-Br-cGMPS). NO release was studied using a fluorescence assay and O2•−–NO interactions by measuring nitrites. After a 16-h incubation with 10 nM U46619, both NCX 911 and sildenafil elicited a concentration-dependent inhibition of O2•− formation and gp91phox expression, NCX 911 being more potent (IC50; 0.26 nM) than sildenafil citrate (IC50; 1.85 nM). These inhibitory effects were reversed by 1 μM ODQ and 10 μM Rp-8-Br-cGMPS. NCX 911 stimulated the formation of cGMP in PAECs and generated NO in a cell-free system to a greater degree than sildenafil citrate. The inhibitory effect of sildenafil was augmented by 1 μM SIN-1 and blocked partially by the eNOS inhibitor 10 μM N5-(1-iminoethyl)-ornithine (L

Six months of daily treatment with vardenafil improves parameters of endothelial inflammation and of hypogonadism in male patients with type 2 diabetes and erectile dysfunction: a randomized, double-blind, prospective trial.

PubMed

Santi, Daniele; Granata, Antonio R M; Guidi, Alessandro; Pignatti, Elisa; Trenti, Tommaso; Roli, Laura; Bozic, Roberto; Zaza, Stefano; Pacchioni, Chiara; Romano, Stefania; Nofer, Jerzy Roch; Rochira, Vincenzo; Carani, Cesare; Simoni, Manuela

2016-04-01

Type 2 diabetes mellitus (T2DM) is associated with endothelial dysfunction, characterized by a reduction of nitric oxide (NO)-mediated relaxation. Phosphodiesterase type 5 inhibitors (PDE5i) improve NO levels. The aim of the study was to investigate whether long-term, chronic treatment with the PDE5i vardenafil improves systemic endothelial function in diabetic men. A prospective, investigator-initiated, randomized, placebo-controlled, double-blind, clinical trial was conducted. In total, 54 male patients affected by T2DM, diagnosed within the last 5 years, and erectile dysfunction were enrolled, regardless of testosterone levels. In all, 26 and 28 patients were assigned to verum and placebo groups respectively. The study consisted of an enrollment phase, a treatment phase (24 weeks) (vardenafil/placebo 10  mg twice in a day) and a follow-up phase (24 weeks). Parameters evaluated were as follows: International Index of Erectile Function 15 (IIEF-15), flow-mediated dilation (FMD), serum interleukin 6 (IL6), endothelin 1 (ET-1), gonadotropins and testosterone (measured by liquid chromatography/tandem mass spectrometry). IIEF-15 erectile function improved during the treatment (P<0.001). At the end of the treatment both FMD (P=0.040) and IL6 (P=0.019) significantly improved. FMD correlated with serum testosterone levels (R(2)=0.299; P<0.001). Testosterone increased significantly under vardenafil treatment and returned in the eugonadal range only in hypogonadal men (n=13), without changes in gonadotropins. Chronic vardenafil treatment did not result in relevant side effects. This is the first double-blind, placebo-controlled clinical trial designed to evaluate the effects of chronic treatment of vardenafil on endothelial health-related parameters and sexual hormones in patients affected by a chronic disease. Chronically administered vardenafil is effective and improves endothelial parameters in T2DM patient. Moreover, chronic vardenafil therapy improves hypogonadism

Involvement of NO-cGMP pathway in anti-hyperalgesic effect of PDE5 inhibitor tadalafil in experimental hyperalgesia.

PubMed

Otari, K V; Upasani, C D

2015-08-01

The association of elevated level of cyclic guanosine monophosphate (cGMP) with inhibition of hyperalgesia and involvement of nitric oxide (NO)-cGMP pathway in the modulation of pain perception was previously reported. Phosphodiesterases 5 (PDE5) inhibitors, sildenafil and tadalafil (TAD) used in erectile dysfunction, are known to act via the NO-cGMP pathway. TAD exerts its action by increasing the levels of intracellular cGMP. Hence, the present study investigated the effect of TAD 5, 10, or 20 mg/kg, per os (p.o.) or L-NAME 20 mg/kg, intraperitoneally (i.p.) and TAD (20 mg/kg, p.o.) in carrageenan- and diabetes-induced hyperalgesia in rats using hot plate test at 55 ± 2 °C. In carrageenan- and diabetes-induced hyperalgesia, TAD (10 and 20 mg/kg, p.o.) significantly increased paw withdrawal latencies (PWLs) as compared to the control group. L-NAME significantly decreased PWLs as compared to the normal group and aggravated the hyperalgesia. Moreover, significant difference in PWLs of L-NAME and TAD 20 was evident. Co-administration of L-NAME (20 mg/kg) with TAD (20 mg/kg) showed significant difference in PWLs as compared to the TAD (20 mg/kg), indicating L-NAME reversed and antagonized TAD-induced anti-hyperalgesia. This suggested an important role of NO-cGMP pathway in TAD-induced anti-hyperalgesic effect.

Sildenafil (Viagra(®)) prevents and restores LPS-induced inflammation in astrocytes.

PubMed

de Santana Nunes, Ana Karolina; Rapôso, Catarina; Björklund, Ulrika; da Cruz-Höfling, Maria Alice; Peixoto, Christina Alves; Hansson, Elisabeth

2016-09-06

Astrocytes are effectively involved in the pathophysiological processes in the central nervous system (CNS) and may contribute to or protect against development of inflammatory and degenerative diseases. Sildenafil is a potent and selective phosphodiesterase-5 (PDE-5) inhibitor, which induces cyclic GMP accumulation. However, the mechanisms of actions on glial cells are not clear. The aim of the present work is to evaluate the role of sildenafil in lipopolysaccharide (LPS)-stimulated astrocytes. The cytoskeleton integrity and Ca(2+) waves were assessed as indicators of inflammatory state. Two main groups were done: (A) one prevention and (B) one restoration. Each of these groups: A1: control; A2: LPS for 24h; A3: sildenafil 1 or 10μM for 4h and then sildenafil 1 or 10μM+LPS for 24h. B1: control; B2: LPS for 24h; B3: LPS for 24h and then LPS+sildenafil 1 or 10μM for 24h. Cytoskeleton integrity was analyzed through GFAP immunolabeling and actin labeling with an Alexa 488-conjugated phalloidin probe. Calcium responses were assessed through a Ca(2+)-sensitive fluorophore Fura-2/AM. The results show that both preventive and restorative treatments with sildenafil (in both concentrations) reduced the Ca(2+) responses in intensity and induced a more organized actin fiber pattern, compared to LPS treated cells. This work demonstrated for the first time that astrocytes are a key part of the sildenafil protective effects in the CNS. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Preventive effect of sildenafil on right ventricular function in rats with monocrotaline-induced pulmonary arterial hypertension

PubMed Central

Yoshiyuki, Rieko; Tanaka, Ryo; Fukushima, Ryuji; Machida, Noboru

2016-01-01

The present study aimed to evaluate the preventive effect of sildenafil treatment on pulmonary hypertension (PH) induced by monocrotaline (MCT) in rats. Fifty-four 12-week-old male Sprague–Dawley rats were injected with MCT or saline solution (MCT-injected rats: n=36; saline: n=18). Serial echocardiography and right ventricular systolic pressure (RVSP) measurements via a cardiac catheter were performed at 2, 4 and 6 weeks after the injection. After injection of MCT, rats received oral sildenafil (MCT/sildenafil group: n=18) or no treatment (MCT group: n=18) until undergoing echocardiography and cardiac catheterization. RVSP in the MCT/sildenafil group was lower than that in the MCT group at 4 (P<0.001) and 6 weeks (P<0.001). The septal curvature was improved in the MCT/sildenafil group compared with the MCT group. This finding showed that sildenafil prevented flattening of the interventricular septum because of right ventricular pressure overload. The ratio of peak trans-tricuspid early diastolic wave velocity to active filling with atrial systolic velocity showed that sildenafil improved diastolic function. Tricuspid annular plane systolic excursion and tricuspid annular systolic velocity in the MCT/sildenafil group did not show preserved myocardial contraction after administration of sildenafil. Administration of sildenafil leads to a reduction in RVSP and improvement in cardiac function in rats with PH induced by MCT. The vasodilatory action of sildenafil improves right ventricular diastolic function, but the intrinsic, positive, inotropic effect of sildenafil is minimal. PMID:26876436

Urinary Tract Symptoms (LUTS) Secondary to Benign Prostatic Hyperplasia (BPH) and LUTS/BPH with Erectile Dysfunction in Asian Men: A Systematic Review Focusing on Tadalafil.

PubMed

Park, Hyun Jun; Won, Ji Eon Joanne; Sorsaburu, Sebastian; Rivera, Paul David; Lee, Seung Wook

2013-12-01

This review assesses lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) with or without erectile dysfunction (ED) and related therapies focusing on tadalafil. A literature search was obtained and reviewed for the epidemiology, treatment therapies, pathophysiology, and efficacy and safety of phosphodiesterase type 5 inhibitor (PDE5i) tadalafil in patients with LUTS/BPH. Approximately 42% of men aged 51 to 60 years have BPH. Approximately 90% of men aged 45 to 80 years have LUTS. Occurrence of LUTS increases with age for almost all racial/ethnic groups (range, 32% to 56%) with prevalence of LUTS highest among Hispanic men, then Blacks, Caucasians, and Asians. There is an independent relationship with LUTS/BPH and ED, with approximately 70% of men with LUTS/BPH having ED with severity of one disease often correlating with the other. The European Urological Association guidelines include the use of the PDE5i tadalafil. Tadalafil is the only therapy recommended for treatment of co-existing BPH and ED, while other therapies have unwanted ED side effects. The mode of action of tadalafil may involve different areas of the lower urinary tract such as smooth muscle cell relaxation in the bladder neck, prostate, and urethra, but there may also be resulting modulation of the afferent nerve activity. Tadalafil (5 mg) in Asian men with LUTS/BPH, similar to global studies, is efficacious and safe. Tadalafil (5 mg) improves co-existing LUTS/BPH and ED, independently. Men with LUTS/BPH likely also have ED. Asian men with LUTS/BPH have similar incidence rates, co-existing ED, comorbid diseases, and risks as non-Asian men. Tadalafil can improve co-existing LUTS/BPH and ED.

Powerful relaxation of phosphodiesterase type 4 inhibitor rolipram in the pig and human bladder neck.

PubMed

Ribeiro, Ana S F; Fernandes, Vítor S; Martínez-Sáenz, Ana; Martínez, Pilar; Barahona, María Victoria; Orensanz, Luis M; Blaha, Igor; Serrano-Margüello, Daniel; Bustamante, Salvador; Carballido, Joaquín; García-Sacristán, Albino; Prieto, Dolores; Hernández, Medardo

2014-04-01

Phosphodiesterase type 5 (PDE5) inhibitors act as effective drugs for the treatment of lower urinary tract symptom (LUTS). There is a poor information, however, about the role of the PDE4 inhibitors on the bladder outflow region contractility. To investigate PDE4 expression and the relaxation induced by the PDE4 inhibitor rolipram versus that induced by the PDE5 blockers sildenafil and vardenafil, in the pig and human bladder neck. Immunohistochemistry for PDE4 expression, myographs for isometric force recordings and fura-2 fluorescence for simultaneous measurements of intracellular Ca2+ concentration ([Ca2+]i ) and tension for rolipram in bladder neck samples were used. PDE4 expression and relaxations to PDE4 and PDE5 inhibitors and simultaneous measurements of [Ca2+]i and tension. PDE4 expression was observed widely distributed in the smooth muscle layer of the pig and human bladder neck. On urothelium-denuded phenylephrine (PhE)-precontracted strips of pig and human, rolipram, sildenafil and vardenafil produced concentration-dependent relaxations with the following order of potency: rolipram> > sildenafil>vardenafil. In pig, the adenylyl cyclase activator forskolin potentiated rolipram-elicited relaxation, whereas protein kinase A (PKA) blockade reduced such effect. On potassium-enriched physiological saline solution (KPSS)-precontracted strips, rolipram evoked a lower relaxation than that obtained on PhE-stimulated preparations. Inhibition of large (BKCa ) and intermediate (IKCa ) conductance Ca2+ -activated K+ channels, neuronal voltage-gated Ca2+ channels, nitric oxide (NO) and hydrogen sulfide (H2 S) synthases reduced rolipram responses. Rolipram inhibited the contractions induced by PhE without reducing the PhE-evoked [Ca2+]i increase. PDE4 is present in the pig and human bladder neck smooth muscle, where rolipram exerts a much more potent relaxation than that elicited by PDE5 inhibitors. In pig, rolipram-induced response is produced through the PKA

Effects of Tadalafil 5 mg Dosed Once Daily in Men with Premature Ejaculation.

PubMed

Ozcan, Levent; Polat, Emre Can; Onen, Efe; Kocaaslan, Ramazan; Otunctemur, Alper; Cekmen, Mustafa; Eraldemir, Ceyla; Ozbek, Emin

2017-01-01

In this study, we evaluated the effect of 5 mg tadalafil once daily in men with premature ejaculation (PE). Thirty married men with lifelong PE and 30 healthy men as control group were included in this study. All the patients received 5 mg tadalafil once a day for a month. The international index of erectile function questionnaire and intravaginal ejaculatory latency times (IELTs) and PE profile were recorded before and after treatment. Plasma samples were collected before and after treatment. The mean baseline IELTs was 40.8 ± 8.1 s in the PE group and 196.5 ± 26.2 s in the control group. After treatment in the PE group, the mean IELTs values showed a statistically significant improvement from the baseline values. At the end of 4 weeks, in the PE group, the mean IELT values showed a statistically significant improvement from the baseline values. Baseline serum nitric oxide (NO) levels were 27.3 ± 1.7 in the PE group and in the 31.1 ± 1.4 healthy control groups. After treatment, NO levels were increased from baseline. We consider that 5 mg tadalafil once daily is safety and effective for the treatment of PE. © 2016 S. Karger AG, Basel.

Sildenafil Citrate Therapy for Oligohydramnios: A Randomized Controlled Trial.

PubMed

Maher, Mohammad Ahmed; Sayyed, Tarek Mohammad; Elkhouly, Nabih

2017-04-01

To compare sildenafil plus hydration with hydration alone in improving the amniotic fluid index and neonatal outcomes in pregnancies complicated by idiopathic oligohydramnios ( amniotic fluid index less than 5 cm without underlying maternal or fetal causes and with normal fetal growth). This was an open-label randomized trial for women carrying singleton pregnancies at 30 weeks of gestation or more with idiopathic oligohydramnios detected during routine ultrasonogram. Women received either oral sildenafil citrate (25 mg every 8 hours) plus intravenous infusion of 2 L isotonic solution or fluids only until delivery. The primary study outcome was the amniotic fluid volume at 6 weeks of follow-up or the final volume before delivery, whichever occurred first. Secondary outcomes were duration of pregnancy prolongation, mode of delivery, and select neonatal outcomes. The study was powered to detect a 45% difference between groups, so, at an α level of 0.05 and 80% power, a sample size of 167 women was required. From February 24, 2015, through April 2016, 196 women were screened and 184 were randomized. Follow-up was completed in 166 (90%): 82 in the sildenafil group and 84 in the hydration group. Baseline characteristics were similar between groups. The amniotic fluid volume was higher in the sildenafil group at the final assessment (11.5 compared with 5.4 cm, P=.02). The sildenafil group delivered later (38.3 compared with 36.0 weeks of gestation, P=.001), had a lower rate of cesarean delivery (28% compared with 73%), and their neonates were less likely to be admitted to the neonatal intensive care unit (11% compared with 41%, P=.001). Sildenafil citrate increases amniotic fluid volume in pregnancies complicated by oligohydramnios. ClinicalTrials.gov, www.clinicaltrials.gov, NCT02372487.

Sildenafil citrate (Viagra) enhances vasodilatation by atrial natriuretic peptide in normal dogs.

PubMed

Ishikura, Fuminobu; Beppu, Shintaro; Asanuma, Toshihiko; Seward, James B; Khandheria, Bijoy K

2007-12-01

Sildenafil citrate (Viagra) is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5, which might enhance the vasorelaxant and natriuretic actions of atrial natriuretic peptide (ANP) in patients with heart failure. The objective of this study was to examine the combined effect of Viagra on hemodynamic changes during infusion of exogenous ANP. Healthy male beagles were used to assess systemic blood pressure, pulmonary artery pressure (PAP), and plasma levels of cGMP. After hemodynamic variables were measured, 0.1 microg.kg(-1).min(-1) of ANP was given during this study. One hour after initiating infusion of ANP, 2 mg/kg of sildenafil citrate or vehicle was given orally via a nasogastric tube. Hemodynamic changes were measured before and 1 h after these administrations. Mean systemic and PAP decreased during infusion of ANP, and further decreased after sildenafil citrate administration, however, mean systemic blood pressure decreased within 10 mmHg. Plasma levels of cGMP also increased after sildenafil citrate administration. In normal dogs, sildenafil citrate enhances the vasodilator effect of ANP by increasing the cGMP level, however, the concomitant use of sildenafil citrate with ANP will not induce severe hypotension.

Urinary Tract Symptoms (LUTS) Secondary to Benign Prostatic Hyperplasia (BPH) and LUTS/BPH with Erectile Dysfunction in Asian Men: A Systematic Review Focusing on Tadalafil

PubMed Central

Park, Hyun Jun; Won, Ji Eon Joanne; Sorsaburu, Sebastian; Rivera, Paul David

2013-01-01

This review assesses lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) with or without erectile dysfunction (ED) and related therapies focusing on tadalafil. A literature search was obtained and reviewed for the epidemiology, treatment therapies, pathophysiology, and efficacy and safety of phosphodiesterase type 5 inhibitor (PDE5i) tadalafil in patients with LUTS/BPH. Approximately 42% of men aged 51 to 60 years have BPH. Approximately 90% of men aged 45 to 80 years have LUTS. Occurrence of LUTS increases with age for almost all racial/ethnic groups (range, 32% to 56%) with prevalence of LUTS highest among Hispanic men, then Blacks, Caucasians, and Asians. There is an independent relationship with LUTS/BPH and ED, with approximately 70% of men with LUTS/BPH having ED with severity of one disease often correlating with the other. The European Urological Association guidelines include the use of the PDE5i tadalafil. Tadalafil is the only therapy recommended for treatment of co-existing BPH and ED, while other therapies have unwanted ED side effects. The mode of action of tadalafil may involve different areas of the lower urinary tract such as smooth muscle cell relaxation in the bladder neck, prostate, and urethra, but there may also be resulting modulation of the afferent nerve activity. Tadalafil (5 mg) in Asian men with LUTS/BPH, similar to global studies, is efficacious and safe. Tadalafil (5 mg) improves co-existing LUTS/BPH and ED, independently. Men with LUTS/BPH likely also have ED. Asian men with LUTS/BPH have similar incidence rates, co-existing ED, comorbid diseases, and risks as non-Asian men. Tadalafil can improve co-existing LUTS/BPH and ED. PMID:24459652

Treatment of Macular Degeneration with Sildenafil: Results of a Two-Year Trial.

PubMed

Coleman, D Jackson; Lee, Winston; Chang, Stanley; Silverman, Ronald H; Lloyd, Harriet O; Daly, Suzanne; Tsang, Stephen H

2018-04-25

To evaluate PDE5/6 inhibition with sildenafil to reduce choroidal ischemia and treat age-related macular degeneration. Sildenafil was prescribed to treat participants with macular degenerations or macular dystrophies measured by spectral-domain optical coherence tomography, color fundus photography, enhanced depth imaging, and best-corrected visual acuity. No change in calcified drusen was noted. Vitelliform-type soft drusen were not substantially changed. A participant with Best vitelliform macular dystrophy had a significant improvement in vision as well as in photoreceptor and ellipsoid layers. Our research supports sildenafil as a safe treatment for age-related and vitelliform macular degenerations. Thickened Bruch's membrane reduces the beneficial effect of perfusion increase, but all eyes appear to benefit from PDE6. Notably, maintenance or improvement in the photoreceptor layer may be the most significant result of sildenafil and is consistent with PDE6 inhibition. Thus, sil-denafil treatment of macular degeneration offers significant potential for vision retention and recovery. © 2018 S. Karger AG, Basel.

Tadalafil enhances the neuroprotective effects of ischemic postconditioning in mice, probably in a nitric oxide associated manner.

PubMed

Gulati, Puja; Singh, Nirmal

2014-05-01

This study investigates the modulatory effect of tadalafil, a selective phosphodiesterase (PDE-5) inhibitor, on the neuroprotective effects of ischemic postconditioning (iPoCo) in mice. Bilateral carotid artery occlusion (BCAO) for 12 min followed by reperfusion for 24 h was employed to produce ischemia and reperfusion induced cerebral injury. Cerebral infarct size was measured using TTC staining. Memory was assessed using the Morris water maze test. Degree of motor incoordination was evaluated using inclined beam-walking, rota-rod, and lateral push tests. Brain nitrite/nitrate, acetylcholinesterase activity, TBARS, and glutathione levels were also estimated. BCAO followed by reperfusion produced a significant increase in cerebral infarct size, brain nitrite/nitrate and TBARS levels, and acetylcholinesterase activity along with a reduction in glutathione. Marked impairment of memory and motor coordination was also noted. iPoCo consisting of 3 episodes of 10 s carotid artery occlusion and reperfusion instituted immediately after BCAO significantly decreased infarct size, memory impairment, motor incoordination, and altered biochemistry. Pretreatment with tadalafil mimicked the neuroprotective effects of iPoCo. The tadalafil-induced neuroprotective effects were significantly attenuated by l-NAME, a nonselective NOS inhibitor. We concluded that tadalafil mimics the neuroprotective effects of iPoCo, probably through a nitric oxide dependent pathway, and PDE-5 could be a target of interest with respect to the neuroprotective mechanism of iPoCo.

Increased collagen maturity with sildenafil citrate: experimental high risk colonic anastomosis model.

PubMed

Cakir, Tebessum; Ozer, Ilter; Bostanci, Erdal Birol; Keklik, Tulay Timucin; Ercin, Ugur; Bilgihan, Ayse; Akoglu, Musa

2015-01-01

Inadequate healing and high anastomosis leak rates at rectal anastomosis may be due to lack of supportive serosal layer and technical difficulty of low anterior resections. Positive effects of sildenafil on wound healing were observed. The aim of this study was to simulate rectal anastomosis as a technical insufficient anastomosis and investigate the effects of sildenafil on anastomosis healing. Colonic anastomoses were carried out in 64 rats and randomized into four groups, CA-S, complete anastomoses without sildenafil (10 mg/kg for 5 days); CA+S, complete anastomoses with sildenafil; IA-S, incomplete anastomoses without sildenafil; IA+S, incomplete anastomoses with sildenafil. Half of the rats in every group were sacrificed on post-operative day (POD) 3, half of them sacrificed on POD 7. Tissues from the anastomoses were used for functional, histochemical, biochemical investigations. Sildenafil treatment resulted in increased bursting pressures in IA+S on POD 7 (p=0.010). Collagen maturity was higher in IA+S on POD 3 and POD 7, CA+S on POD 7 (p=0.010; p=0.010; p<0.007). Collagen content was higher in IA+S on POD 7 (p<0.001). Glutathione, hydroxyproline levels were similar. Malondialdehyde levels were lower in IA+S on POD 3 (p<0.001). Epithelization score was higher in IA+S on POD 7 (p=0.007). Inflammation score was higher in CA-S group on POD 3 and POD 7 (p<0.001; p<0.001). Neutrophil score was lower in CA+S on POD 3 (p=0.005). An increase in collagen content, maturity, and epithelization, a decrease in neutrophil infiltration, oxidative stress and better mechanical strength were observed with the administration of sildenafil. Copyright © 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.

[Analysis and identification of illegal constituents in health food products implicitly advertizing tonic or slimming effect in the National Institute of Health Sciences in Japan].

PubMed

Goda, Yukihiro

2014-01-01

With the prefectural governments' aid of the purchase, the Division of Pharmacognosy, Phytochemistry and Narcotics, National Institute of Health Sciences (NIHS) successively has surveyed illegal constituents in health food products implicitly advertizing tonic or slimming effect since the fiscal year of 2002 (slimming type) or 2003 (tonic type). The average numbers of the analyzed products per year are about 100 (slimming type) and 150 (tonic type), respectively. We also continuously distribute standards of authentic samples of several illegal components such as N-nitrosofenfluramine (NFF) and sildenafil (SIL) to prefectural institutes and the average gross number per year is about 140. In the case of slimming type, the fact that the products containing NFF were widely sold in Japanese markets in 2002 is well known. In addition, phenolphthalein, fenfluramine, sibtramine, desdimethylsibtramine, orlistat, mazindol, Rhubarb, Senna Leaf, etc. have been found as illegal constituents. In the tonic type products, we have identified more than 20 synthetic compounds relating to the erectile dysfunction (ED) treatment drugs, SIL, vardenafil and tadalafil (TDF). Since 2005, their synthetic intermediates and the patented but non-approved PDE5 inhibitors also have been found. It should be noted that TDF was found in the shells of capsule in 2009 and that mutaprodenafil was found as pro-drug type illegal component in 2010. In this report identification method of these illegal constituents is briefly described and then analytical trend in this decade is reviewed.

Gateways to Clinical Trials.

PubMed

Bayés, M; Rabasseda, X; Prous, J R

2002-09-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Adalimumab, aeroDose insulin inhaler, agomelatine, alendronic acid sodium salt, aliskiren fumarate, alteplase, amlodipine, aspirin, atazanavir; Bacillus Calmette-Guérin, basiliximab, BQ-788, bupropion hydrochloride; Cabergoline, caffeine citrate, carbamazepine, carvedilol, celecoxib, cyclosporine, clopidogrel hydrogensulfate, colestyramine; Dexamethasone, diclofenac sodium, digoxin, dipyridamole, docetaxel, dutasteride; Eletriptan, enfuvirtidie, eplerenone, ergotamine tartrate, esomeprazole magnesium, estramustine phosphate sodium; Finasteride, fluticasone propionate, fosinopril sodium; Ganciclovir, GBE-761-ONC, glatiramer acetate, gliclazide, granulocyte-CSF; Heparin sodium, human isophane insulin (pyr), Hydrochlorothiazide; Ibuprofen, inhaled insulin, interferon alfa, interferon beta-1a; Laminvudine, lansoprazole, lisinopril, lonafarnib, losartan potassium, lumiracoxib; MAb G250, meloxicam methotrexate, methylprednisolone aceponate, mitomycin, mycophenolate mofetil; Naproxen sodium, natalizumab, nelfinavir mesilate, nemifitide ditriflutate, nimesulide; Omalizumab, omapatrilat, omeprazole, oxybutynin chloride; Pantoprazole sodium, paracetamol, paroxetine, pentoxifylline, pergolide mesylate, permixon, phVEGF-A165, pramipexole hydrochloride, prasterone, prednisone, probucol, propiverine hydrochloride; Rabeprazole sodium, resiniferatoxin, risedronate sodium, risperidone, rofecoxib rosiglitazone maleate, ruboxistaurin mesilate hydrate; Selegiline transdermal system, sertraline, sildenafil citrate, streptokinase; Tadalafil, tamsulosin hydrochloride, technosphere/Insulin, tegaserod maleate, tenofovir disoproxil

Effect of topically applied sildenafil citrate on wound healing: experimental study.

PubMed

Gürsoy, Koray; Oruç, Melike; Kankaya, Yüksel; Ulusoy, Mustafa Gürhan; Koçer, Uğur; Kankaya, Duygu; Gürsoy, Reyhan Neslihan; Çevik, Özge; Öğüş, Elmas; Fidanci, Vildan

2014-08-16

Wound healing is a complex process that necessitates organization of different cell types and several signalling molecules. The aim of this study is to evaluate the effect of different concentrations of sildenafil citrate, which decreases cGMP degradation, on wound healing by secondary intention.This study was performed using 25 Sprague Dawley rats weighing 200-250 grams. 4 dorsal defects were created. Four different treatment modalities which were 1% and 5% sildenafil citrate gel prepared with carbopol, pure carbopol gel without any drug in it and 0,9% NaCl solution; were applied to each lesion of the same rat. Randomly selected five rats (25 rats in total) were sacrificed on 3rd, 5th, 7th, 10th, and 14th days; and the effect of each modality was evaluated by means of defect area measurement, histopathological examination and measurement of tissue hydroxyproline levels.Sildenafil citrate gel application decreased the defect areas in a dose independent manner starting from 3rd day and dose dependent manner after 7th day. By means of vascularization, sildenafil citrate increased vascularity starting from 3rd day. The strength of acute inflammation was superior in sildenafil groups starting from 5th day; and the amount and maturation of granulation in the wound bed, as well as the strength of chronic inflammation were superior in defects treated with sildenafil citrate as early as 7th day.

Effect of topically applied sildenafil citrate on wound healing: experimental study

PubMed Central

Gürsoy, Koray; Oruç, Melike; Kankaya, Yüksel; Ulusoy, M. Gürhan; Koçer, Uğur; Kankaya, Duygu; Gürsoy, R. Neslihan; Çevik, Özge; Öğüş, Elmas; Fidanci, Vildan

2014-01-01

Wound healing is a complex process that necessitates organization of different cell types and several signalling molecules. The aim of this study is to evaluate the effect of different concentrations of sildenafil citrate, which decreases cGMP degradation, on wound healing by secondary intention. This study was performed using 25 Sprague Dawley rats weighing 200-250 grams. 4 dorsal defects were created. Four different treatment modalities which were 1% and 5% sildenafil citrate gel prepared with carbopol, pure carbopol gel without any drug in it and 0,9% NaCl solution; were applied to each lesion of the same rat. Randomly selected five rats (25 rats in total) were sacrificed on 3rd, 5th, 7th, 10th, and 14th days; and the effect of each modality was evaluated by means of defect area measurement, histopathological examination and measurement of tissue hydroxyproline levels. Sildenafil citrate gel application decreased the defect areas in a dose independent manner starting from 3rd day and dose dependent manner after 7th day. By means of vascularization, sildenafil citrate increased vascularity starting from 3rd day. The strength of acute inflammation was superior in sildenafil groups starting from 5th day; and the amount and maturation of granulation in the wound bed, as well as the strength of chronic inflammation were superior in defects treated with sildenafil citrate as early as 7th day. PMID:25172969

An open-label study to evaluate sildenafil for the treatment of lymphatic malformations.

PubMed

Danial, Christina; Tichy, Andrea L; Tariq, Umar; Swetman, Glenda L; Khuu, Phuong; Leung, Thomas H; Benjamin, Latanya; Teng, Joyce; Vasanawala, Shreyas S; Lane, Alfred T

2014-06-01

Lymphatic malformations can be challenging to treat. Mainstay interventions including surgery and sclerotherapy are invasive and can result in local recurrence and complications. We sought to assess the effect of 20 weeks of oral sildenafil on reducing lymphatic malformation volume and symptoms in children. Seven children (4 boys, 3 girls; ages 13-85 months) with lymphatic malformations were given oral sildenafil for 20 weeks in this open-label study. The volume of the lymphatic malformation was calculated blindly using magnetic resonance imaging performed before and after 20 weeks of sildenafil. Lymphatic malformations were assessed clinically on weeks 4, 12, 20, and 32. Both the physician and parents evaluated the lymphatic malformation in comparison with baseline. Four subjects had a lymphatic malformation volume decrease (1.0%-31.7%). In 2 subjects, despite a lymphatic malformation volume increase (1.1%-3.7%), clinical improvement was noted while on sildenafil. One subject had a 29.6% increase in lymphatic malformation volume and no therapeutic response. Lymphatic malformations of all 6 subjects who experienced a therapeutic response on sildenafil softened and became easily compressible. Adverse events were minimal. A randomized controlled trial will be necessary to verify the effects of sildenafil on lymphatic malformations. Sildenafil can reduce lymphatic malformation volume and symptoms in some children. Copyright © 2014 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

Effect of sildenafil citrate (Viagra) on coronary flow in normal subjects.

PubMed

Ishikura, Fuminobu; Beppu, Shintaro; Ueda, Hiroaki; Nehra, Ajay; Khandheria, Bijoy K

2008-01-01

The purpose of this study was to evaluate the effect of sildenafil citrate (Viagra) on coronary function in normal subjects. The study assessed mean blood pressure, left anterior descending coronary artery (LAD) flow, and echocardiographic variables before and 30 and 60 minutes after taking 50 mg of sildenafil citrate. The mean velocity of LAD flow was assessed with Doppler flow imaging. The study subjects were 6 healthy male volunteers (mean age 37 years). The mean velocity of LAD flow increased 60 minutes after taking sildenafil citrate, but there were no other changes. Two volunteers felt mild flashing and one had mild headache during the study. Sildenafil citrate caused vasodilatation in a normal coronary artery without systemic pressure drops. These results suggest that the agent itself did not have negative effects on the heart in normal subjects.

Time-dependent interactions of the hypotensive effects of sildenafil citrate and sublingual glyceryl trinitrate

PubMed Central

Oliver, James J; Kerr, Debra M; Webb, David J

2009-01-01

AIM To investigate the time course of the hypotensive interaction between sildenafil and glyceryl trinitrate (GTN). METHODS Two double-blind, placebo-controlled, randomized, crossover studies were performed. Subjects were challenged with sublingual GTN 400 µg at different times after oral sildenafil 100 mg. After each GTN challenge frequent measures of blood pressure (BP) were made. In the first study GTN was given 1–48 h after sildenafil/placebo to 33 healthy men. In the second study GTN was given 1–8 h after sildenafil/placebo to 20 men with stable angina. RESULTS In healthy men there was a greater mean maximum reduction in BP with sildenafil/GTN than with placebo/GTN only at 1 h. In angina patients, there was a greater mean maximum reduction in BP with sildenafil/GTN than with placebo/GTN for up to 8 h. The mean (95% confidence interval) differences in maximum systolic BP reduction (mmHg) at 1, 4, 6 and 8 h were −16 (−12, −21), −12 (−4, −20), −6 (1, −12) and −9 (−3, −15), all P < 0.05 except at 6 h (NS). At 6 and 8 h the interaction was not more than additive, and hypotensive symptoms did not occur. CONCLUSIONS In men with angina there is an interaction on BP reduction between sildenafil and GTN for ≥ 8 h after sildenafil administration, but this is no more than additive from 6 h. These data may be helpful to clinicians who are considering the use of GTN in patients presenting with angina who have received sildenafil within 24 h. PMID:19371313

Effect of Sildenafil on Pre-Eclampsia-Like Mouse Model Induced By L-Name.

PubMed

Motta, C; Grosso, C; Zanuzzi, C; Molinero, D; Picco, N; Bellingeri, R; Alustiza, F; Barbeito, C; Vivas, A; Romanini, M C

2015-08-01

N(omega)-nitro-L-arginine methyl ester (L-NAME) decreases the vasodilator effect of nitric oxide (NO) and induces pre-eclampsia in mouse. Sildenafil inhibits the degradation of nitric oxide and increases vasodilation. This study aimed to determine the effects of sildenafil citrate on angiogenesis and oxidative stress at the maternal foetal interface on pre-eclampsia-like mouse model induced by L-NAME. Twenty pregnant mice were divided into four groups: (i) vehicle control; (ii) L-NAME; (iii) sildenafil; (4) L-NAME+sildenafil. L-NAME was administered from day 7 of pregnancy and sildenafil from day 8 until day 16; animals were euthanized on day 17. Placental and foetal sizes and weights were measured; lipid peroxide levels and catalase activity in placental homogenates were determined, and placental vascular endothelia were identified by lectin-histochemistry using BSA-I lectin. Western blot analysis was used to determine VEGF expression in placental homogenates. No changes were seen in placental and foetal development in mice with normal pregnancies treated with sildenafil. Treatments with L-NAME reduced significantly the placental weight and average height and decreased the percentage of the endothelial surface. These alterations may be mediated by the reduction of NO levels in trophoblastic cells, due to the inhibitory effect of L-NAME on nitric oxide synthase (NOS) synthesis. This effect was offset by the treatment with sildenafil, with an increase in the percentage of the endothelial surface. In conclusion, our results indicate that treatment with sildenafil on pre-eclampsia mouse model can be used without adverse effects on the concept and its use in the treatment of pre-eclampsia is promising. © 2015 Blackwell Verlag GmbH.

Sildenafil (Viagra) sensitizes prostate cancer cells to doxorubicin-mediated apoptosis through CD95

PubMed Central

Das, Anindita; Durrant, David; Mitchell, Clint; Dent, Paul; Batra, Surinder K.; Kukreja, Rakesh C.

2016-01-01

We previously reported that Sildenafil enhances apoptosis and antitumor efficacy of doxorubicin (DOX) while attenuating its cardiotoxic effect in prostate cancer. In the present study, we investigated the mechanism by which sildenafil sensitizes DOX in killing of prostate cancer (PCa) cells, DU145. The death receptor Fas (APO-1 or CD95) induces apoptosis in many carcinoma cells, which is negatively regulated by anti-apoptotic molecules such as FLIP (Fas-associated death domain (FADD) interleukin-1-converting enzyme (FLICE)-like inhibitory protein). Co-treatment of PCa cells with sildenafil and DOX for 48 hours showed reduced expression of both long and short forms of FLIP (FLIP-L and -S) as compared to individual drug treatment. Over-expression of FLIP-s with an adenoviral vector attentuated the enhanced cell-killing effect of DOX and sildenafil. Colony formation assays also confirmed that FLIP-S over-expression inhibited the DOX and sildenafil-induced synergistic killing effect as compared to the cells infected with an empty vector. Moreover, siRNA knock-down of CD95 abolished the effect of sildenafil in enhancing DOX lethality in cells, but had no effect on cell killing after treatment with a single agent. Sildenafil co-treatment with DOX inhibited DOX-induced NF-κB activity by reducing phosphorylation of IκB and nuclear translocation of the p65 subunit, in addition to down regulation of FAP-1 (Fas associated phosphatase-1, a known inhibitor of CD95-mediated apoptosis) expression. This data provides evidence that the CD95 is a key regulator of sildenafil and DOX mediated enhanced cell death in prostate cancer. PMID:26716643

Protective effects of sildenafil citrate administration on cisplatin-induced ovarian damage in rats.

PubMed

Taskin, Mine Islimye; Yay, Arzu; Adali, Ertan; Balcioglu, Esra; Inceboz, Umit

2015-04-01

The aim of this study is to evaluate the effects of sildenafil citrate on cisplatin-induced ovarian toxicity. Thirty-two female rats were divided into four groups. Group 1: saline control; group 2: cisplatin; group 3: sildenafil citrate; and group 4: cisplatin plus sildenafil citrate group. In groups 2 and 4, the rats were injected with 5 mg/kg cisplatin intraperitoneally (i.p.). In groups 3 and 4, the rats were injected with 1.4 mg/kg sildenafil citrate i.p. The ovaries were removed two weeks later in all groups. Histopathologic examination, follicle counting and classification were performed. The expression of anti-Müllerian hormone (AMH) was detected immunohistochemically in the ovarian tissues. Sildenafil alleviated cisplatin-induced histopathological changes in the ovarian tissue. Primordial, secondary and tertiary follicles were diminished in group 2 compared with group 1 (p < 0.05). Pretreatment with sildenafil citrate preserved primordial follicle count in group 4 compared with group 2, and the difference was statistically significant (p < 0.05). According to our results, immunoreactivity intensity of AMH was lower in group 2 compared with group 1 (92.4 ± 3.97 versus 88.8 ± 1.77) but not significantly, whereas immunoreactivity intensity of AMH was higher in group 4 compared with group 2 (88.8 ± 1.77 versus 94.1 ± 2.36; p < 0.05). Our results demonstrated that pretreatment with sildenafil citrate is beneficial for protecting the ovaries from cisplatin-induced damage. Sildenafil citrate can be a choice for fertility preservation.

Sildenafil potentiates the antitumor activity of cisplatin by induction of apoptosis and inhibition of proliferation and angiogenesis

PubMed Central

El-Naa, Mona Mohamed; Othman, Mohamed; Younes, Sheren

2016-01-01

Sildenafil is the first phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction. However, recent studies have been suggesting an antitumor effect of sildenafil. The current study assessed the aforementioned activity of sildenafil in vivo and in vitro in solid-tumor-bearing mice and in a human cell line MCF-7, respectively. Moreover, we investigated the impact of sildenafil on cisplatin antitumor activity. The solid tumor was induced by inoculation of Ehrlich ascites carcinoma cells in female mice. The tumor-bearing mice were assigned randomly to control (saline), sildenafil (sildenafil 5 mg/kg/d, PO daily for 15 days), cisplatin (cisplatin 7.5 mg/kg, IP once on the 12th day of Ehrlich ascites carcinoma inoculation), and combination therapy (cisplatin and sildenafil) groups. The tumor volume was measured at the end of the treatment period along with the following parameters: angiogenin, vascular endothelial growth factor, tumor necrosis factor-α, Ki-67, caspase-3, DNA-flow cytometry analysis, and histopathological examination. The study results showed that sildenafil has significantly decreased the tumor volume by 30.4%, angiogenin and tumor necrosis factor-α contents, as well as vascular endothelial growth factor expression. Additionally, caspase-3 level significantly increased with sildenafil treatment, whereas Ki-67 expression failed to show any significant changes. Furthermore, the cell cycle analysis revealed that sildenafil was capable of improving the category of tumor activity from moderate to low proliferative. Sildenafil induced necrosis in the tumor. Moreover, the drug of interest showed cytotoxic activity against MCF-7 in vitro as well as potentiated cisplatin antitumor activity in vivo and in vitro. These findings shed light on the antitumor activity of sildenafil and its possible impact on potentiating the antitumor effect of conventional chemotherapeutic agents such as cisplatin. These effects might be related to antiangiogenic

Sildenafil potentiates the antitumor activity of cisplatin by induction of apoptosis and inhibition of proliferation and angiogenesis.

PubMed

El-Naa, Mona Mohamed; Othman, Mohamed; Younes, Sheren

2016-01-01

Sildenafil is the first phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction. However, recent studies have been suggesting an antitumor effect of sildenafil. The current study assessed the aforementioned activity of sildenafil in vivo and in vitro in solid-tumor-bearing mice and in a human cell line MCF-7, respectively. Moreover, we investigated the impact of sildenafil on cisplatin antitumor activity. The solid tumor was induced by inoculation of Ehrlich ascites carcinoma cells in female mice. The tumor-bearing mice were assigned randomly to control (saline), sildenafil (sildenafil 5 mg/kg/d, PO daily for 15 days), cisplatin (cisplatin 7.5 mg/kg, IP once on the 12th day of Ehrlich ascites carcinoma inoculation), and combination therapy (cisplatin and sildenafil) groups. The tumor volume was measured at the end of the treatment period along with the following parameters: angiogenin, vascular endothelial growth factor, tumor necrosis factor-α, Ki-67, caspase-3, DNA-flow cytometry analysis, and histopathological examination. The study results showed that sildenafil has significantly decreased the tumor volume by 30.4%, angiogenin and tumor necrosis factor-α contents, as well as vascular endothelial growth factor expression. Additionally, caspase-3 level significantly increased with sildenafil treatment, whereas Ki-67 expression failed to show any significant changes. Furthermore, the cell cycle analysis revealed that sildenafil was capable of improving the category of tumor activity from moderate to low proliferative. Sildenafil induced necrosis in the tumor. Moreover, the drug of interest showed cytotoxic activity against MCF-7 in vitro as well as potentiated cisplatin antitumor activity in vivo and in vitro. These findings shed light on the antitumor activity of sildenafil and its possible impact on potentiating the antitumor effect of conventional chemotherapeutic agents such as cisplatin. These effects might be related to antiangiogenic

Urethral dysfunction due to alloxan-induced diabetes. Urodynamic evaluation and action of sildenafil citrate.

PubMed

Gomes de Souza Pegorare, Ana Beatriz; Gonçalves, Marco Antonio; Martiniano de Oliveira, Alessandra; Rodrigues Junior, Antonio Antunes; Tucci, Silvio; Suaid, Haylton Jorge

2014-04-01

To evaluate the effect of diabetes mellitus and of sildenafil citrate on female urethral function. Twenty nine female rats were divided into four groups: G1 - (n=9), normal rats; G2 - (n=6), normal rats treated with sildenafil citrate; G3 - (n=9) rats with alloxan-induced diabetes; G4 - (n=5) rats with alloxan-induced diabetes treated with sildenafil citrate. Under anesthesia, urodynamic evaluation was performed by cystometry and urethral pressure simultaneously. A significant increase in urethral pressure was observed during micturition. Sildenafil citrate can partially reduced urethral pressure in diabetic female rats.

Sildenafil Can Affect Innate and Adaptive Immune System in Both Experimental Animals and Patients

PubMed Central

Boguska, Agnieszka

2017-01-01

Sildenafil, a type 5 phosphodiesterase inhibitor (PDE5-I), is primarily used for treating erectile dysfunction. Sildenafil inhibits the degradation of cyclic guanosine monophosphate (cGMP) by competing with cGMP for binding site of PDE5. cGMP is a secondary messenger activating protein kinases and a common regulator of ion channel conductance, glycogenolysis, and cellular apoptosis. PDE5 inhibitors (PDE-Is) found application in cardiology, nephrology, urology, dermatology, oncology, and gynecology. Positive result of sildenafil treatment is closely connected with its immunomodulatory effects. Sildenafil influences angiogenesis, platelet activation, proliferation of regulatory T cells, and production of proinflammatory cytokines and autoantibodies. Sildenafil action in humans and animals appears to be different. Surprisingly, it also acts differently in males and females organisms. Although the immunomodulatory effects of PDE5 inhibitors appear to be promising, none of them reached the point of being tested in clinical trials. Data on the influence of selective PDE5-Is on the human immune system are limited. The main objective of this review is to discuss the immunomodulatory effects of sildenafil in both patients and experimental animals. This is the first review of the current state of knowledge about the effects of sildenafil on the immune system. PMID:28316997

Sildenafil improves renal function in patients with pulmonary arterial hypertension

PubMed Central

Webb, David J; Vachiery, Jean-Luc; Hwang, Lie-Ju; Maurey, Julie O

2015-01-01

Aim Elevated serum creatinine (sCr) and low estimated glomerular filtration rate (eGFR) are associated with poor outcomes in patients with pulmonary arterial hypertension (PAH) whereas sildenafil treatment improves PAH outcomes. This post hoc analysis assessed the effect of sildenafil on kidney function and links with clinical outcomes including 6-min walk distance, functional class, time to clinical worsening and survival. Methods Patients with PAH received placebo or sildenafil 20, 40 or 80 mg three times daily in the SUPER-1 study and open-label sildenafil titrated to 80 mg three times daily (as tolerated) in the extension study. Results Baseline characteristics were similar among groups (n = 277). PAH was mostly idiopathic (63%) and functional class II (39%) or III (58%). From baseline to week 12, kidney function improved (increased eGFR, decreased sCr) with sildenafil and worsened with placebo. In univariate logistic regression, improved kidney function was associated with significantly improved exercise and functional class (odds ratios 1.17 [95% CI 1.01, 1.36] and 1.21 [95% CI 1.03, 1.41], respectively, for sCr and 0.97 [95% CI 0.94, 0.99] and 0.97 [95% CI 0.94, 0.99] for eGFR, all P < 0.05). In patients who maintained or improved kidney function, time to worsening was significantly delayed (P < 0.02 for both kidney parameters). Observed trends towards improved survival were not significant. Patients with eGFR <60 (vs. ≥60) ml min–1 1.73 m–2 appeared to have worse survival. Conclusions Sildenafil treatment was associated with improved kidney function in patients with PAH, which was in turn associated with improved exercise capacity and functional class, a reduced risk of clinical worsening, and a trend towards reduced mortality. PMID:25727860

Pharmacokinetics of Intravenous Sildenafil in Children with Palliated Single Ventricle Heart Defects: Effect of Elevated Hepatic Pressures

PubMed Central

Hill, Kevin D.; Sampson, Mario R.; Li, Jennifer S.; Tunks, Robert D.; Schulman, Scott R.; Cohen-Wolkowiez, Michael

2015-01-01

Aims Sildenafil is frequently prescribed to children with single ventricle heart defects. These children have unique hepatic physiology with elevated hepatic pressures which may alter drug pharmacokinetics. We sought to determine the impact of hepatic pressure on sildenafil pharmacokinetics in children with single ventricle heart defects. Methods A population pharmacokinetic model was developed using data from 20 single ventricle children receiving single dose intravenous sildenafil during cardiac catheterization. Nonlinear mixed effect modeling was used for model development and covariate effects were evaluated based on estimated precision and clinical significance. Results The analysis included a median (range) of 4 (2–5) pharmacokinetic samples per child. The final structural model was a two-compartment model for sildenafil with a one-compartment model for des-methyl-sildenafil (active metabolite), with assumed 100% sildenafil to des-methyl-sildenafil conversion. Sildenafil clearance was unaffected by hepatic pressure (clearance = 0.62 L/H/kg); however, clearance of des-methyl-sildenafil (1.94 × (hepatic pressure/9)−1.33 L/h/kg) was predicted to decrease ~7 fold as hepatic pressure increased from 4 to 18 mm Hg. Predicted drug exposure was increased by ~1.5 fold in subjects with hepatic pressures ≥ 10 mm Hg versus < 10 mm Hg (median area under the curve = 533 μg*h/L versus 792 μg*h/L). Discussion Elevated hepatic pressure delays clearance of the sildenafil metabolite, des-methyl-sildenafil and increases drug exposure. We speculate that this results from impaired biliary clearance. Hepatic pressure should be considered when prescribing sildenafil to children. These data demonstrate the importance of pharmacokinetic assessment in patients with unique cardiovascular physiology that may affect drug metabolism. PMID:26197839

Impact of Mitochondrial Ca2+-Sensitive Potassium (mBKCa) Channels in Sildenafil-Induced Cardioprotection in Rats

PubMed Central

Behmenburg, Friederike; Dorsch, Marianne; Huhn, Ragnar; Mally, David; Heinen, André; Hollmann, Markus W.; Berger, Marc M.

2015-01-01

Background Mitochondrial large-conductance Ca2+-sensitive potassium (mBKCa) channels are involved in myocardial ischemic preconditioning. Their role in sildenafil-induced cardioprotection is unknown. We investigated whether sildenafil-induced acute cardioprotection is mediated by activation of mBKCa channels in the rat heart in vitro. Methods Male Wistar rats (n = 8 per group) were randomized and anesthetized with pentobarbital (90 mg/kg). Hearts were isolated, mounted on a Langendorff system and perfused with Krebs-Henseleit buffer at a constant pressure of 80 mmHg. Hearts underwent 30 min of global ischemia followed by 60 min of reperfusion. At the end of the experiments infarct size was determined by TTC staining. In the control group rats were not further treated. Sildenafil (3 μM) was administered over 10 min before the beginning of ischemia. The mBKCa channel inhibitor paxilline (1 μM) was administered with and without sildenafil before the onset of ischemia. The pathway underlying sildenafil-induced cardioprotection was further investigated with the protein kinase G blocker KT5823 (1 μM). Myocardial cGMP concentration was measured by ELISA. Data (mean±SD) were analysed with a one and two-way analysis of variance as appropriate. Results In control animals infarct size was 52±8%. Sildenafil increased cGMP concentration and reduced infarct size to 35±6% (P<0.05 vs. control). Paxilline and KT5823 completely blocked sildenafil-induced cardioprotection (paxilline+sildenafil: 50±8%, KT5823+sildenafil: 45±8%; both P<0.05 vs. sildenafil). Functional heart parameters and coronary flow were not different between the study groups. Conclusion This study shows that in male rats protein kinase G-dependent opening of mBKCa channels plays a pivotal role in sildenafil-induced cardioprotection. PMID:26671662

Efficacy and Safety of Tadalafil 5 mg Once Daily for the Treatment of Erectile Dysfunction After Robot-Assisted Laparoscopic Radical Prostatectomy: A 2-Year Follow-Up.

PubMed

Kim, Soodong; Sung, Gyung Tak

2018-03-27

Although nerve-sparing robot-assisted radical prostatectomy (NS-RALP) is performed, a large number of patients still experience erectile dysfunction (ED) after surgery. To evaluate the efficacy and safety of tadalafil 5 mg once daily (OaD) in ED treatment over 2 years and investigate the cause of vascular ED after NS-RARP. We retrospectively evaluated 95 men who underwent NS-RARP and had a penile rehabilitation treatment with tadalafil 5 mg OaD. They were classified into 3 groups: tadalafil 5 mg OaD for 2 years (group I), tadalafil 5 mg OaD for 1 year (group II), and no tadalafil (group III). All patients in group I underwent penile color duplex ultrasound to evaluate the cause of vascular ED. Patients were surveyed using the abridged 5-item International Index of Erectile Function (IIEF-5). Statistically significant improvements were observed in group I for all IIEF-5 domain scores (P = .000). There was no statistically significant difference in recovery of erectile function (EF) the 2-year follow-up between groups I and II. Sub-analysis based on NS status showed no difference in recovery of EF. However, group I showed better trends in EF improvement. Those with venogenic ED had poor responses compared with those with arteriogenic ED or unremarkable findings with tadalafil 5-mg OaD treatment (14.2% vs 55.0% vs 53.3%). The overall side effects included hot flushing in 9.5%, headache in 7.1%, and dizziness in 2.3% of patients. Long-term usage of tadalafil 5 mg OaD after RARP can be an effective option for penile rehabilitation. The present study is a retrospective study with a relatively small sample. Although the responses of patients with venogenic ED were limited compared with those with arteriogenic ED, tadalafil 5-mg OaD treatment was well tolerated and significantly improved EF up to 2 years after NS-RARP. Kim S, Sung GT. Efficacy and Safety of Tadalafil 5 mg Once Daily for the Treatment of Erectile Dysfunction After Robot-Assisted Laparoscopic Radical

SILDENAFIL CITRATE INDUCED RETINAL TOXICITY-ELECTRORETINOGRAM, OPTICAL COHERENCE TOMOGRAPHY, AND ADAPTIVE OPTICS FINDINGS.

PubMed

Yanoga, Fatoumata; Gentile, Ronald C; Chui, Toco Y P; Freund, K Bailey; Fell, Millie; Dolz-Marco, Rosa; Rosen, Richard B

2018-02-27

To report a case of persistent retinal toxicity associated with a high dose of sildenafil citrate intake. Single retrospective case report. A 31-year-old white man with no medical history presented with complaints of bilateral multicolored photopsias and erythropsia (red-tinted vision), shortly after taking sildenafil citrate-purchased through the internet. Patient was found to have cone photoreceptor damage, demonstrated using electroretinogram, optical coherence tomography, and adaptive optics imaging. The patient's symptoms and the photoreceptor structural changes persisted for several months. Sildenafil citrate is a widely used erectile dysfunction medication that is typically associated with transient visual symptoms in normal dosage. At high dosage, sildenafil citrate can lead to persistent retinal toxicity in certain individuals.

[The effects of sildenafil citrate on the isolated rat aorta: comparative in vitro study].

PubMed

Ozbek, H; Güler, N; Aydin, S; Eryonucu, B; Bilge, M

2001-03-01

Sildenafil, an inhibitor of cGMP-specific phosphodiesterase 5 (PDE5), is currently being used as oral therapy for penile erectile dysfunction. The aim of this study was to investigate the relaxing effect of sildenafil on vascular tissue and compare it with the known vasodilatator agents, sodium nitroprusside and acetylcholine. Rat thoracic aorta samples were cut into rings, mounted on steel hooks, and immersed in aerated Krebs solution maintained at 37 degree C. Isometric responses were recorded by strain gauge transducers connected to a polygraph. Graded relaxations were induced using increasing concentrations of acetylcholine sodium nitroprusside and sildenafil. The agents all does-dependently relaxed rat aorta strips. The relaxing potential of sildenafil was found to be similar to sodium nitroprusside, but higher than acetylcholine. In the absence of regulatory mechanisms, sildenafil citrate has noticeable vasodilatatory effect in vitro.

Studies on sildenafil citrate (Viagra) interaction with DNA using electrochemical DNA biosensor.

PubMed

Rauf, Sakandar; Nawaz, Haq; Akhtar, Kalsoom; Ghauri, Muhammad A; Khalid, Ahmad M

2007-05-15

The interaction of sildenafil citrate (Viagra) with DNA was studied by using an electrochemical DNA biosensor. The binding mechanism of sildenafil citrate was elucidated by using constant current potentiometry and differential pulse voltammetry at DNA-modified glassy carbon electrode. The decrease in the guanine oxidation peak area or peak current was used as an indicator for the interaction in 0.2M acetate buffer (pH 5). The binding constant (K) values obtained were 2.01+/-0.05 x 10(5) and 1.97+/-0.01 x 10(5)M(-1) with constant current potentiometry and differential pulse voltammetry, respectively. A linear dependence of the guanine peak area or peak current was observed within the range of 1-40 microM sildenafil citrate with slope=-2.74 x 10(-4)s/microM, r=0.989 and slope=-2.78 x 10(-3)microA/microM, r=0.995 by using constant current potentiometry and differential pulse voltammetry, respectively. Additionally, binding constant values for sildenafil citrate-DNA interaction were determined for the pH range of 4-8 and in biological fluids (serum and urine) at pH 5. The influence of sodium and calcium ions was also studied to elucidate the mechanism of sildenafil citrate-DNA interaction under different solution conditions. The present study may prove to be helpful in extending our understanding of the anticancer activity of sildenafil citrate from cellular to DNA level.

Sildenafil effects on sexual and cardiovascular responses in women with spinal cord injury.

PubMed

Sipski, M L; Rosen, R C; Alexander, C J; Hamer, R M

2000-06-01

Sexual dysfunction is common in women with spinal cord injuries (SCIs) and other neurologic conditions. Sildenafil has previously been shown to be safe and effective in the treatment of erectile dysfunction due to SCI. This study is the first to evaluate the sexual and cardiovascular effects of sildenafil in women with SCIs in a controlled, laboratory setting. Nineteen premenopausal women with SCIs were randomly assigned to receive either sildenafil (50 mg) or placebo in a double-blind, crossover design study. Physiologic and subjective measures of sexual response, heart rate, and blood pressure were recorded during baseline and sexual stimulation conditions. Adverse events were also recorded. Significant increases in subjective arousal (SA) were observed with both drug (P <0.01) and sexual stimulation conditions (P <0.001), and a borderline significant (P <0.07) effect of drug administration on vaginal pulse amplitude (VPA) was noted. Maximal responses occurred when sildenafil was combined with visual and manual sexual stimulation. Cardiovascular data showed modest increases in heart rate (+/-5 bpm) and mild decreases in blood pressure (+/-4 mm Hg) across all stimulation conditions, consistent with the peripheral vasodilatory mechanism of the drug. Sildenafil was well tolerated with no evidence of significant adverse events. Findings suggest that sildenafil may partially reverse the sexual dysfunction commonly associated with SCI in women. Consistent with previous findings in men, the sexual effects of the drug were most evident under conditions of optimal stimulation. Mild, clinically insignificant cardiovascular effects were also noted. Further large-scale studies of sildenafil's effects in women with neurogenic sexual dysfunction are strongly indicated.

Sildenafil citrate use in Addis Ababa: characteristics of users and pharmacists' dispensing practices.

PubMed

Gebregeorgise, Dawit Teshome; Belay, Yajeb Melesse; Kälvemark Sporrong, Sofia

2018-02-01

Background Studies have reported misuse of sildenafil citrate for recreational purpose, not least by healthy young men. This is becoming a major concern, for medical and other reasons. Objective The aim of this study was to document the characteristics of sildenafil citrate users and to explore the dispensing practices of the medicine in selected community pharmacies in Addis Ababa, Ethiopia. Setting Data was collected in community pharmacies in Addis Ababa, Ethiopia. Method A survey, using a self-administrated questionnaire, was conducted among customers who purchased sildenafil citrate from community pharmacies. Simple descriptive statistics were used to analyse data. Also, semi-structured interviews were conducted with community pharmacists. These were analysed thematically. Main outcome measures Socio-demographic characteristics (survey), themes (interviews). Results All survey respondents (n = 197) were men, 57.9% were below 40 years old, 53.8% had never been married and 58.4% had used sildenafil citrate before. A minority (16.2%) were diagnosed with erectile dysfunction. The main reason for buying sildenafil citrate was experimentation (45.7%). Pharmacists reported that sildenafil citrate was often dispensed without a prescription. The reason for this was, according to the interviewees, competition in the market. Also, the medicine was often dispensed without adequate information or counselling. Conclusions Selling and buying sildenafil citrate without a prescription seems to be common practice in pharmacies in Addis Ababa. It is crucial to strengthen the regulatory activity to protect customers from health risks. In addition pharmacy professionals should be supported to work in accordance with professional and legal standards.

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2006-03-01

, mycophenolate mofetil, mycophenolic acid sodium salt; Nitisinone; Omalizumab, omapatrilat, ONYX-015, oxaliplatin; Paclitaxel, paclitaxel nanoparticles, panitumumab, parathyroid hormone (human recombinant), peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, pertuzumab, phosphatidylcholine-rich phospholipid mixture, pimecrolimus, pioglitazone hydrochloride, pramlintide acetate, prasterone; QR-333; Ranelic acid distrontium salt, ranolazine, rasagiline mesilate, RFB4(dsFv)-PE38, ribavirin, rifabutin, risperidone, rituximab, rofecoxib, rosiglitazone maleate, rosiglitazone maleate/metformin hydrochloride, rotavirus vaccine; S-236, salmeterol xinafoate, sarizotan hydrochloride, sildenafil, sildenafil citrate, sunitinib malate; Tadalafil, tegaserod maleate, temozolomide, tenofovir disoproxil fumarate, teriparatide, tiotropium bromide, tipifarnib, trabectedin, treprostinil sodium; Vandetanib, vardenafil hydrochloride hydrate, vatalanib succinate, vinflunine, virosome influenza vaccine, voriconazole; Zidovudine. (c) 2006 Prous Science. All rights reserved.

The Global Online Sexuality Survey (GOSS): the United States of America in 2011 chapter II: phosphodiesterase inhibitors utilization among English speakers.

PubMed

Shaeer, Osama

2013-02-01

Utility of phosphodiesterase inhibitors (PDEi's) for the treatment of erectile dysfunction (ED) has been the focus of experimental and clinical studies. However, public preferences, attitudes, and experiences with PDEi's are rarely addressed from a population/epidemiology viewpoint. The Global Online Sexuality Survey (GOSS) is a worldwide epidemiologic study of sexuality and sexual disorders, first launched in the Middle East in 2010, followed by the United States in 2011. To describe the utilization rates, trends, and attitudes toward PDEi's in the United States in the year 2011. GOSS was randomly deployed to English-speaking male Web surfers in the United States via paid advertising on Facebook®, comprising 146 questions. Utilization rates and preferences for PDEi's by brand. Six hundred three subjects participated; mean age 53.43 years ± 13.9. Twenty-three point seven percent used PDEi's on more consistent basis, 37.5% of those with ED vs. 15.6% of those without ED (recreational users). Unrealistic safety concerns including habituation were pronounced. Seventy-nine point six percent of utilization was on prescription basis. PDEi's were purchased through pharmacies (5.3% without prescription) and in 16.5% over the Internet (68% without prescription). Nine point six percent nonprescription users suffered coronary heart disease. Prescription use was inclined toward sildenafil, generally, and particularly in severe cases, and shifted toward tadalafil in moderate ED and for recreational use, followed by vardenafil. Nonprescription utilization trends were similar, except in recreational use where sildenafil came first. In the United States unrealistic safety concerns over PDEi's utility exist and should be addressed. Preference for particular PDEi's over the others is primarily dictated by health-care providers, despite lack of guidelines that govern physician choice. Online and over-the-counter sales of PDEi's are common, and can expose a subset of users to health

Sildenafil citrate use and the incidence of nonarteritic anterior ischemic optic neuropathy

PubMed Central

Gorkin, L; Hvidsten, K; Sobel, RE; Siegel, R

2006-01-01

Summary Nonarteritic anterior ischemic optic neuropathy (NAION) has been reported rarely in men after taking sildenafil or other phosphodiesterase 5 inhibitors for erectile dysfunction (ED). The incidence of NAION in men receiving sildenafil treatment for ED was estimated using pooled safety data from global clinical trials and European observational studies. Based on clinical trial data in more than 13,000 men and on more than 35,000 patient-years of observation in epidemiologic studies, we estimated an incidence of 2.8 cases of NAION per 100,000 patient-years of sildenafil exposure. This is similar to estimates reported in general US population samples (2.52 and 11.8 cases per 100,000 men aged ≥50 years). The data cited herein do not suggest an increased incidence of NAION in men who took sildenafil for ED. PMID:16620369

Safety and effectiveness of tadalafil in patients with pulmonary arterial hypertension: Japanese post-marketing surveillance data.

PubMed

Yamazaki, Hiroyoshi; Kobayashi, Noriko; Taketsuna, Masanori; Tajima, Koyuki; Murakami, Masahiro

2017-05-01

To evaluate the long-term safety and effectiveness of tadalafil in patients with pulmonary arterial hypertension (PAH) in real-world clinical practice. This prospective, multicenter, noninterventional, post-marketing surveillance included patients with PAH who were observed for up to 2 years after initiation of tadalafil. Safety was assessed by analyzing the frequency of adverse drug reactions (ADRs), discontinuations due to adverse events (AEs), and serious adverse drug reactions (SADRs). Effectiveness measurements included the assessment of the change in World Health Organization (WHO) functional classification of PAH, 6-minute walk test, cardiac catheterization, and echocardiography. Among 1676 patients analyzed for safety, the overall incidence of ADRs was 31.2%. The common ADRs (≥1.0%) were headache (7.0%), diarrhea (1.9%), platelet count decreased (1.8%), anemia, epistaxis, and nausea (1.6% each), flushing (1.3%), hepatic function abnormal (1.1%), hot flush, and myalgia (1.0% each). The common SADRs (≥0.3%) were cardiac failure (0.7%), interstitial lung disease, worsening of PAH, and platelet count decreased (0.3% each). Among 1556 patients analyzed for effectiveness, the percentages of patients with improvement of WHO functional class at 3 months, 1 year, and 2 years after the initiation of tadalafil, and last observation were 17.1%, 24.8%, 28.9%, and 22.5%, respectively. At all observation points (except pulmonary regurgitation pressure gradient at end diastole at 3 months), the mean 6-minute walk distance, cardiac catheterization, and echocardiogram measurements showed statistically significant improvement. This surveillance demonstrated that tadalafil has favorable safety and effectiveness profiles for long-term use in patients with PAH in Japan.

Effect of Sildenafil Citrate on Intraocular Pressure and Blood Pressure in Human Volunteers

PubMed Central

Gerometta, Rosana; Alvarez, Lawrence J.; Candia, Oscar A.

2011-01-01

Anecdotal reports have suggested that the vasodilator, sildenafil citrate, which evokes its effect via a select inhibition of PDE5, has the potential to increase intraocular pressure (IOP) in some individuals. An ocular hypertensive effect by sildenafil was also recently described in a sheep animal model. In contrast, clinical studies have not found a direct association between sildenafil ingestion (commonly consumed as Viagra) and changes in IOP. However, some such studies also reported no effects of sildenafil on systemic blood pressure (BP) at the time of the IOP determination. Given this surprising result, our purpose was to repeat a study in human volunteers in the city of Corrientes, Argentina to corroborate the effects of sildenafil on human IOP and systemic BP. For the present study, 9 healthy volunteers (male and female, 18 to 74 years old) were selected as subjects after ophthalmic and cardiovascular evaluation indicated that they exhibited normal parameters for their age. In a masked, placebo-controlled study, the subjects ingested 100 mg sildenafil citrate (provided as Vorst from Laboratorios Bernabo, Argentina) in one session, and a placebo on a second separate occasion. IOP was measured with a Goldman applanation tonometer by an ophthalmologist, and BP by a second physician, neither of whom witnessed the tablet ingestion by the volunteers, nor provided with information on the nature of the test compounds. A third individual administered the tablets. The average baseline IOP of this group of 9 was 13.1 ± 0.6 mm Hg. Subsequent to sildenafil ingestion, IOP increased by 26% to 16.5 ± 0.8 mm Hg 60 min later (p< 0.005, as paired data), and returned to control values within 2 hrs. Both systolic and diastolic BP were significantly reduced by sildenafil ingestion. At the point of maximal systemic hypotension (90 min), the systolic and diastolic pressures declined by 15% and 13%, respectively. No significant changes in IOP or BP were recorded after ingestion

Rivastigmine but not vardenafil reverses cannabis-induced impairment of verbal memory in healthy humans.

PubMed

Theunissen, E L; Heckman, P; de Sousa Fernandes Perna, E B; Kuypers, K P C; Sambeth, A; Blokland, A; Prickaerts, J; Toennes, S W; Ramaekers, J G

2015-01-01

One of the most often reported cognitive deficits of acute cannabis administration is an impaired recall of previously learned information. The aim of the present study was to determine whether cannabis-induced memory impairment in humans is mediated via glutamatergic or cholinergic pathways. Fifteen occasional cannabis users participated in a double-blind, placebo-controlled, six-way cross-over study. On separate test days, subjects received combinations of pretreatment (placebo, vardenafil 20 mg or rivastigmine 3 mg) and treatment (placebo or 1,376 mg cannabis/kg body weight). Cognitive tests were administered immediately after inhalation of treatment was finished and included measures of memory (visual verbal learning task, prospective memory test, Sternberg memory test), perceptual-motor control (critical tracking task), attention (divided attention task) and motor impulsivity (stop signal task). The results of this study demonstrate that subjects under the influence of cannabis were impaired in all memory tasks, in critical tracking, divided attention and the stop signal task. Pretreatment with rivastigmine attenuated the effect of cannabis on delayed recall and showed a trend towards significance on immediate recall. When cannabis was given in combination with vardenafil, there were no significant interaction effects in any of the tasks. The present data therefore suggest that acetylcholine plays an important role in cannabis-induced memory impairment, whereas similar results for glutamate have not been demonstrated in this study.

Influence of the PDE5 inhibitor tadalafil on redox status and antioxidant defense system in C2C12 skeletal muscle cells.

PubMed

Duranti, Guglielmo; Ceci, Roberta; Sgrò, Paolo; Sabatini, Stefania; Di Luigi, Luigi

2017-05-01

Phosphodiesterase type 5 inhibitors (PDE5Is), widely known for their beneficial effects onto male erectile dysfunction, seem to exert favorable effects onto metabolism as well. Tadalafil exposure increases oxidative metabolism of C2C12 skeletal muscle cells. A rise in fatty acid (FA) metabolism, requiring more oxygen, could induce a larger reactive oxygen species (ROS) release as a byproduct thus leading to a redox imbalance. The aim of this study was to determine how PDE5I tadalafil influences redox status in skeletal muscle cells to match the increasing oxidative metabolism. To this purpose, differentiated C2C12 skeletal muscle cells were treated with tadalafil and analyzed for total antioxidant capacity (TAC) and glutathione levels as marker of redox status; enzyme activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) engaged in antioxidant defense; and lipid peroxidation (TBARS) and protein carbonyls (PrCar) as markers of oxidative damage. Tadalafil increased total intracellular glutathione (tGSH), CAT, SOD, and GPx enzymatic activities while no changes were found in TAC. A perturbation of redox status, as showed by the decrease in the ratio between reduced/oxidized glutathione (GSH/GSSG), was observed. Nevertheless, it did not cause any change in TBARS and PrCar levels probably due to the enhancement in the antioxidant enzymatic network. Taken together, these data indicate that tadalafil, besides improving oxidative metabolism, may be beneficial to skeletal muscle cells by enhancing the enzymatic antioxidant system capacity.

Genuine sildenafil tablets sold in Brazil disguised as MDMA.

PubMed

Coelho Neto, José; Faraco, Renata F P; Alves, Cíntia F; Castro, Stela M M; Machado, Yuri

2018-02-01

MDMA and sildenafil are two examples among many substances consumed in "raves", as well as in other types of "recreative" social events nowadays. During the first six months of 2017, five cases of supposedly MDMA tablets seized by local law enforcement forces in the state of Minas Gerais, Brazil, and brought to our forensic laboratory for examination, attracted our attention among dozens of others, as the tablets apprehended in these cases were, in fact, colorfully painted versions of genuine, pentagon-shaped, sildenafil tablets, freely available for sale in local pharmacies and drugstores. Physical profiling, together with ATR-FTIR spectral matching, multi-component/deconvolution analysis and correlation were employed to prove that these tablets were genuine sildenafil tablets from a specific manufacturer, painted in a colorful way so that they could be marketed as MDMA tablets to unsuspecting buyers. Copyright © 2017 Elsevier B.V. All rights reserved.

Should the patient with coronary artery disease use sildenafil?

PubMed

Cheitlin, Melvin D

2003-01-01

Since the etiology of erectile dysfunction is frequently related to endothelial dysfunction, a problem in common with much vascular disease, erectile dysfunction disproportionately affects patients with cardiovascular disease. With the development of phosphodiesterase 5 inhibitors, the first of which was sildenafil (Viagra), an effective oral medication became available. The question of safety of these drugs, especially in patients with latent or overt coronary artery disease, is of concern. Sildenafil relaxes smooth muscle and therefore lowers systolic and diastolic blood pressure slightly. With organic nitrates, the drop in blood pressure is potentiated, at times dangerously, thereby making it contraindicated to take nitrates within 24 hours of using sildenafil. In double-blind, placebo-controlled trials, there was no difference between sildenafil subjects and control patients in the incidence of myocardial infarction, cardiovascular, and total deaths. Coronary disease patients with stable angina, controlled on medications, were included in the trials. Therefore, sildenafil, as a drug, is safe in such patients. With a patient with coronary artery disease suddenly engaging in the physical exercise associated with sexual intercourse, there is the danger of increased risk of precipitating myocardial infarction or death. The cardiovascular metabolic cost of sexual activity is reviewed and appears to be approximately at the level of 3-5 metabolic equivalents of exercise. Sexual activity occurs within 2 hours of the onset of an acute myocardial infarction in <1.0% of patients. Although sexual intercourse is estimated to increase the risk of myocardial infarction by a factor of 2x, there is still only a very small increase in risk, a risk acceptable to patients who feel their quality of life will be markedly improved by their ability to engage in sexual activity.

The effect of sildenafil citrate (Viagra) on cerebral blood flow in patients with cerebrovascular risk factors.

PubMed

Lorberboym, M; Mena, I; Wainstein, J; Boaz, M; Lampl, Y

2010-06-01

Sildenafil citrate is widely used for erectile dysfunction. The present study examined the short-term effects of sildenafil administration in individuals with cerebrovascular risk factors, including patients with a history of stroke. Twenty-five consecutive male patients with erectile dysfunction and vascular risk factors were included in the study. A perfusion brain SPECT study was performed at baseline and 1 h after the oral administration of sildenafil. Associations between any of the risk factors and the perfusion scores were not detected, with the exception of stroke. Stroke patients showed significantly more areas with diminished perfusion after sildenafil administration compared to baseline. In patients with diabetes or hypertension, a dose of 50 mg sildenafil does not appear to produce detrimental effects on cerebral blood flow. However, patients with a history of stroke may be at increased risk of hemodynamic impairment after the use of sildenafil.

Sildenafil prevents the up-regulation of transient receptor potential canonical channels in the development of cardiomyocyte hypertrophy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kiso, Hironori; Ohba, Takayoshi; Iino, Kenji

2013-07-05

Highlights: •Transient receptor potential canonical (TRPC1, 3 and 6) are up-regulated by ET-1. •Sildenafil inhibited hypertrophic responses (BNP, Ca entry, NFAT activation). •Sildenafil suppressed TRPC1, 3 and 6 expression. -- Abstract: Background: Transient receptor potential canonical (TRPCs) channels are up-regulated in the development of cardiac hypertrophy. Sildenafil inhibits TRPC6 activation and expression, leading to the prevention of cardiac hypertrophy. However, the effects of sildenafil on the expression of other TRPCs remain unknown. We hypothesized that in addition to its effects of TRPC6, sildenafil blocks the up-regulation of other TRPC channels to suppress cardiomyocyte hypertrophy. Methods and results: In cultured neonatalmore » rat cardiomyocytes, a 48 h treatment with 10 nM endothelin (ET)-1 induced hypertrophic responses characterized by nuclear factor of activated T cells activation and enhancement of brain natriuretic peptide expression and cell surface area. Co-treatment with sildenafil (1 μM, 48 h) inhibited these ET-1-induced hypertrophic responses. Although ET-1 enhanced the gene expression of TRPCs, sildenafil inhibited the enhanced gene expression of TRPC1, C3 and C6. Moreover, co-treatment with sildenafil abolished the augmentation of SOCE in the hypertrophied cardiomyocytes. Conclusions: These results suggest that sildenafil inhibits cardiomyocyte hypertrophy by suppressing the up-regulation of TRPC expression.« less

The effect of physician and patient education when combined with vardenafil treatment in Canadian males with erectile dysfunction: an open-label, factorial-designed, cluster-randomized clinical trial.

PubMed

Brock, Gerald; Carrier, Serge; Alarie, Pierre; Pommerville, Peter; Casey, Richard; Harris, Stewart; Ward, Richard

2008-03-01

Studies evaluating the effect of education on treatment success with phosphodiesterase type 5 (PDE5) inhibitor therapy in men with erectile dysfunction (ED) are limited. Additional education of the primary care physician (PCP) and the patient are thought to optimize the treatment of ED. To assess the impact of education of the PCP or of the patient in the treatment of ED with vardenafil relative to usual care. In this 12-week, open-label, multicenter, factorial-designed, cluster-randomized Canadian study, 1,029 patients with ED were enrolled into four different education groups: usual care, patient education, PCP education, and both PCP and patient education. All groups started on vardenafil 10 mg, with the option to titrate at weeks 4 and 8. The primary efficacy measure was the difference at week 4 last observation carried forward (LOCF) in the overall improvement in erectile function (EF) as measured by the Global Assessment Question (GAQ), while on background vardenafil, between those receiving education vs. those who did not. Other secondary assessments included responses to diary questions regarding penetration (sexual encounter profile, SEP2) and erection maintenance (SEP3), and to questionnaires regarding treatment satisfaction (Erectile Dysfunction Inventory of Treatment Satisfaction [EDITS]). A total of 956 patients were included in the intent-to-treat population. Mean baseline International Index of Erectile Function-EF domain score was 13. GAQ response rates at week 4 LOCF were high (>80%) for all groups, regardless of the education given. Mean per patient SEP2 and SEP3 rates at week 12 LOCF were 86-89% and 79-83%, respectively. In an exploratory analysis, a positive relationship between GAQ responses and EDITS scores was observed (P < or = 0.0007). Vardenafil was generally well tolerated. In men with moderate ED, vardenafil led to high success rates and satisfaction regardless of the education given. The benefits of education for PCP and patients in

Utero-placental perfusion Doppler indices in growth restricted fetuses: effect of sildenafil citrate.

PubMed

El-Sayed, Mohamed Adel; Saleh, Said Abdel-Aty; Maher, Mohammad Ahmed; Khidre, Asmaa Mohamed

2018-04-01

To assess efficacy and tolerability of sildenafil citrate on utero-placental blood flow and fetal growth in pregnancies complicated by fetal growth restriction (FGR). From March 2015, a randomized controlled trial of 54 patients at 24 weeks or more complicated by FGR and abnormal Doppler indices were randomly allocated 1:1 into an intervention arm (receive sildenafil citrate, 50 mg) or a control arm (receive placebo). The primary outcomes were changes occurred in the Doppler parameters 2 h following drug administration. Baseline characteristics were similar between groups. Significant difference was observed in the Delta uterine and umbilical Doppler indices among sildenafil group as compared to placebo group (p < 0.001). Middle cerebral Doppler indices, however, decreased significantly after sildenafil, which could be the result of shifting more blood to improve the utero-placental perfusion. No difference regarding Delta cerebro-placental ratio among both groups (p = 0.979). Sildenafil was also associated with pregnancy prolongation (p = .0001), increased gestational age at delivery (p = .004), improved neonatal weight (p = .0001), and less admission to neonatal intensive care unit (p = .03). No adverse effects reported in both treatment arms. Sildenafil citrate, by its vasodilator effect, can improve utero-placental blood flow in pregnancies complicated by FGR and abnormal Doppler. gov Registry: NCT02362399.

The effects of cimetidine and antacid on the pharmacokinetic profile of sildenafil citrate in healthy male volunteers

PubMed Central

Wilner, Keith; Laboy, Lucia; LeBel, Marc

2002-01-01

Aims To examine the effect of concomitant cimetidine or antacid administration on the pharmacokinetic profile of sildenafil citrate in healthy male volunteers in two open-label, randomized studies. Methods The first study was a parallel-group design in which 22 healthy male volunteers received sildenafil (50 mg) on days 1 and 5 and cimetidine (800 mg) or placebo on days 3, 4, 5, and 6. Blood samples were collected predose and at specified times up to 48 h postdose on days 1 and 5 to determine plasma levels of sildenafil and its metabolite, UK-103,320. The second study was a two-way crossover design in which 12 volunteers received sildenafil with or without a 30-ml dose of a magnesium hydroxide/aluminium hydroxide antacid. Blood samples were collected and analysed as in the first study. The two study periods were separated by at least 14 days. Results Coadministration of cimetidine had no statistically significant effect on the tmax or kel of sildenafil but caused a statistically significant increase in sildenafil AUCt and Cmax of 56% and 54%, respectively (P<0.01). Differences between the two treatment groups were smaller for the metabolite than for sildenafil, although cimetidine treatment did significantly (P<0.05) increase the AUCt for UK-103,320 by 30%. Antacid coadministration had no statistically significant effect on any pharmacokinetic parameter of sildenafil or UK-103,320. Whether taken alone, with cimetidine, or with an antacid, sildenafil was well tolerated. Most adverse events were mild in nature, and no subject withdrew from either study for any reason related to the drug. Conclusions Cimetidine co-administration produced an increase in sildenafil plasma levels; however, this increase is not sufficient to warrant dosage adjustment of either drug. Antacid coadministration had no effect on the pharmacokinetic profile of sildenafil. PMID:11879257

Substantially increased sildenafil bioavailability after sublingual administration in children with congenital heart disease: two case reports

PubMed Central

2014-01-01

Introduction Pulmonary hypertension is a progressive disease of diverse origin with devastating consequences in adults as well as in children. The phosphodiesterase 5 inhibitor sildenafil successfully lowers pulmonary vascular resistance. However, because of its poor enteral absorption, resulting in ineffective plasma concentrations, responses in infants and children are often erratic. Case presentations We report the cases of two Caucasian boys, one born at term (case 1) and one aged 2.5 years (case 2), who had structural cardiac and pulmonary defects accompanied by symptomatic pulmonary hypertension. They received sildenafil enterally and sublingually and also intravenously in one of them. Plasma samples were taken at various time points to determine the plasma concentrations of sildenafil and its partially active metabolite. Sildenafil and N-desmethyl sildenafil were quantified using a validated liquid chromatography/mass spectrometry method. Oxygen partial pressure was determined from routine arterial blood gas samples. Conclusion In agreement with previous observations in adults, we found that sublingual sildenafil was more extensively absorbed in our two pediatric patients. After sublingual administration, sildenafil plasma concentrations increased by 314% to 361% compared to enteral dosing. Concurrently, the metabolic ratio increased, suggesting not only that the overall absorption was enhanced but also that first-pass metabolism was partially bypassed. In case 2, the free fraction of sildenafil was 0.9%, which is considerably less than in adults (4%), suggesting that, in case 2, higher plasma concentration would have been needed to achieve effects similar to those in adults. Sublingual sildenafil appears to be a promising alternative route of administration in children with poor enteral absorption. PMID:24885923

Sildenafil citrate for the management of antidepressant-associated erectile dysfunction.

PubMed

Nurnberg, H George; Hensley, Paula L

2003-01-01

Sexual side effects of serotonin reuptake inhibitors, such as antidepressant-associated erectile dysfunction, are common and negatively impact treatment compliance. Current management approaches have important limitations, and most lack clear and meaningful efficacy in double-blind, placebo-controlled trials. A MEDLINE search (English language, 1966-2003) was performed using the terms antidepressive agents, erectile dysfunction, and sildenafil. Emphasis was placed on studies that used specific sexual function measurements and were placebo controlled. Sildenafil citrate, a selective and competitive inhibitor of phosphodiesterase type 5, enhances the cyclic guanosine monophosphate-mediated relaxation of cavernosal smooth muscles in response to sexual stimulation, permitting vascular engorgement and penile erection. The efficacy and tolerability of sildenafil in the treatment of antidepressant-associated erectile dysfunction have been confirmed in double-blind, placebo-controlled trials.

A spontaneous, double-blind, double-dummy cross-over study on the effects of daily vardenafil on arterial stiffness in patients with vasculogenic erectile dysfunction.

PubMed

Aversa, Antonio; Letizia, Claudio; Francomano, Davide; Bruzziches, Roberto; Natali, Marco; Lenzi, Andrea

2012-10-18

It is known that the incidence of endothelial dysfunction in patients with vascular erectile dysfunction (ED) is increased. The effects of daily vardenafil on endothelial function and arterial stiffness in patients with erectile dysfunction (ED) have never been investigated. 20 men complaining vascular ED (mean IIEF5=12 ± 6 and peak systolic velocity-PSV=24 ± 2 cm/s) were enrolled in a 4-week, randomized, double-blind, double-dummy, crossover study (mean age 59 ± 11) and received either vardenafil 10mg daily or 20mg on-demand with a two-week washout interval. Primary endpoints were variation from baseline of reactive hyperemia (RH) and augmentation index (AI) calculated by fingertip peripheral arterial tonometry (PAT) device. Secondary endpoints were variations of IIEF-5 and SEP3 scores from baseline and plasma surrogate markers of endothelial function, i.e. endothelin-1 (ET-1) and adrenomedullin (ADM). Patients who took daily vardenafil (vs. on-demand) reported significant (P<0.01) improvements in arterial stiffness as evaluated by AI and reduction of plasma ADM levels (p<0.05) but no improvement in average RH. When corrected for heart rate, ADM showed a strong direct relationship with AI (r(2)=0.22; p<0.005). The proportion of patients with an IIEF5 score of ≥ 22 or in SEP3 percentage of success rates were similar. Each treatment resulted in significantly greater IIEF5 scores (p<0.001) and better SEP3 response rates (p<0.0001) compared with baseline. We demonstrated that daily vardenafil improves arterial stiffness and erectile function measurements in men with severe vasculogenic ED. This effect may be mediated, at least in part, by a reduction in ADM circulating levels. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Identification of Sildenafil (Viagra) and Its Metabolite (UK 103,320) in Six Aviation Fatalities

DTIC Science & Technology

2006-02-01

Identification of Sildenafil ( Viagra ®) and Its Metabolite (UK-103,320) in Six Aviation Fatalities Robert D. Johnson Russell J. Lewis Civil...DOT/FAA/AM-06/3 4. Title and Subtitle 5. Report Date February 2006 Identification of Sildenafil ( Viagra ®) and Its Metabolite (UK-103,320...report presents a rapid and reliable method for the identification and quantitation of sildenafil ( Viagra ®) and its active metabolite, UK-103,320. This

Measurement of Choroidal Perfusion and Thickness Following Systemic Sildenafil (Viagra®)

PubMed Central

Kim, David Y.; Silverman, Ronald H.; Chan, R.V. Paul; Khanifar, Aziz A.; Rondeau, Mark; Lloyd, Harriet; Schlegel, Peter; Coleman, D. Jackson

2011-01-01

Objective To demonstrate anatomic and physiologic changes in the human choroid following systemic sildenafil citrate (ViagraR) using enhanced depth imaging spectral domain-optical coherence tomography (EDI-OCT) and swept-scan high frequency digital ultrasound. Methods Seven healthy male subjects (mean age 32.7 years) were evaluated at baseline and two hours after ingesting 50 mg of sildenafil. Swept-scan high frequency digital ultrasound and EDI-OCT were utilized to measure choroidal perfusion and thickness, respectively. Results were read by masked observers. The Wilcoxon signed-rank test and t-test were used to analyze differences in choroidal flow and thickness at baseline and two hours after ingestion of sildenafil. Results Two hours following sildenafil, increased choroidal perfusion was observed in 11 of 12 eyes measured by swept-scan high frequency digital ultrasound. The mean increase was 3.46 (±2.00) times baseline with a range of 0.47 to 7.80 times baseline (p=0.004). Increased choroidal thickness was observed in 12 of 12 eyes measured with EDI-OCT. The average choroidal thickness increased by 11.6% temporal to the fovea, 9.3% nasal to the fovea, and 10.7% underneath the fovea (p<0.001 for all values). Conclusions Choroidal perfusion and thickness both increase in response to systemic sildenafil. These changes could secondarily affect retinal function, explain previously reported clinical symptoms, and potentially be a useful adjunct for treatment of ocular diseases that would benefit from increased choroidal blood flow. PMID:22974308

Effect of sildenafil citrate on intraocular pressure and blood pressure in human volunteers.

PubMed

Gerometta, Rosana; Alvarez, Lawrence J; Candia, Oscar A

2011-07-01

Anecdotal reports have suggested that the vasodilator, sildenafil citrate, which evokes its effect via a select inhibition of PDE5, has the potential to increase intraocular pressure (IOP) in some individuals. An ocular hypertensive effect by sildenafil was also recently described in a sheep animal model. In contrast, clinical studies have not found a direct association between sildenafil ingestion (commonly consumed as Viagra) and changes in IOP. However, some such studies also reported no effects of sildenafil on systemic blood pressure (BP) at the time of the IOP determination. Given this surprising result, our purpose was to repeat a study in human volunteers in the city of Corrientes, Argentina to corroborate the effects of sildenafil on human IOP and systemic BP. For the present study, 9 healthy volunteers (male and female, 18-74 years old) were selected as subjects after ophthalmic and cardiovascular evaluation indicated that they exhibited normal parameters for their age. In a masked, placebo-controlled study, the subjects ingested 100 mg sildenafil citrate (provided as Vorst from Laboratorios Bernabo, Argentina) in one session, and a placebo on a second separate occasion. IOP was measured with a Goldman applanation tonometer by an ophthalmologist, and BP by a second physician, neither of whom witnessed the tablet ingestion by the volunteers, nor provided with information on the nature of the test compounds. A third individual administered the tablets. The average baseline IOP of this group of 9 was 13.1 ± 0.6 mm Hg. Subsequent to sildenafil ingestion, IOP increased by 26% to 16.5 ± 0.8 mm Hg 60 min later (P < 0.005, as paired data), and returned to control values within 2 h. Both systolic and diastolic BP were significantly reduced by sildenafil ingestion. At the point of maximal systemic hypotension (90 min), the systolic and diastolic pressures declined by 15% and 13%, respectively. No significant changes in IOP or BP were recorded after

Development and characterization of polymer-coated liposomes for vaginal delivery of sildenafil citrate.

PubMed

Refai, Hanan; Hassan, Doaa; Abdelmonem, Rehab

2017-11-01

Vaginal administration of sildenafil citrate has shown recently to develop efficiently the uterine lining with subsequent successful embryo implantation following in vitro fertilization. The aim of the present study was to develop sildenafil-loaded liposomes coated with bioadhesive polymers for enhanced vaginal retention and improved drug permeation. Three liposomal formulae were prepared by thin-film method using different phospholipid:cholesterol ratios. The optimal liposomal formulation was coated with bioadhesive polymers (chitosan and HPMC). A marked increase in liposomal size and zeta potential was observed for all coated liposomal formulations. HPMC-coated liposomes showed the greater bioadhesion and higher entrapment efficiency than chitosan-coated formulae. The in vitro release studies showed prolonged release of sildenafil from coated liposomes as compared to uncoated liposomes and sildenafil solution. Ex vivo permeation study revealed the enhanced permeation of coated relative to uncoated liposomes. Chitosan-coated formula demonstrated highest drug permeation and was thus selected for further investigations. Transmission electron microscopy (TEM) and Fourier transform infrared spectroscopy (FTIR) confirmed the successful coating of the liposomes by chitosan. Histopathological in vivo testing proved the efficacy of chitosan-coated liposomes to improve blood flow to the vaginal endometrium and to increase endometrial thickness. Chitosan-coated liposomes can be considered as potential novel drug delivery system intended for the vaginal administration of sildenafil, which would prolong system's retention at the vaginal site and enhance the permeation of sildenafil to uterine blood circulation.

Comparing the Efficacy of Tadalafil Versus Placebo on Pulmonary Artery Systolic Pressure and Right Ventricular Function in Patients with Beta-Thalassaemia Intermedia.

PubMed

Jalalian, Rozita; Moghadamnia, Ali Akbar; Tamaddoni, Ahmad; Khafri, Soraya; Iranian, Mohammadreza

2017-07-01

Conventional oral therapies in the management of pulmonary hypertension in people without haemoglobinopathies are of limited value in thalassaemia patients because of toxicity and poor effectiveness. This study was conducted to assess the effect of tadalafil on pulmonary artery pressure and right ventricular systolic function in patients with beta-thalassaemia intermedia. Forty-four patients with beta-thalassaemia intermedia with pulmonary hypertension based on transthoracic echocardiography (TTE) were entered in the study. Patients with hepatic or renal insufficiency and also patients who were treated with organic nitrates or alpha-blockers were excluded. The patients were randomly divided into two groups (n=22) and they were treated for six weeks with tadalafil (40mg daily) or placebo. The pulmonary artery systolic pressure (PASP), tricuspid regurgitation velocity (TRV) and parameters related to systolic function of the right ventricle were measured by the TTE before and after treatment. Significant improvement in TRV (3.02±0.02 m/s-2.52±0.06 m/s), PASP (45.31±0.66 mmHg-34.26±1.15mmHg) and parameters related to systolic function of the right ventricle were observed in the group who received tadalafil compared to placebo (p< 0.05). Tadalafil significantly decreased PASP and TRV in patients with beta-thalassaemia intermedia. Likewise, tadalafil improved right ventricular systolic function in the patients. Copyright © 2016 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

Microcirculatory effects of sildenafil in experimental testicular torsion in rats.

PubMed

Oroszi, Márton; Szabó, Andrea; Fehér, Ádám Miklós; Deák, Gábor; Bajory, Zoltán

2018-05-21

Investigate the short-term effect of sildenafil on microcirculation, especially the velocity, the pattern of the flow and the recruitment of the leukocyte in postcapillaries. In male Sprague-Dawley rats, the microcirculatory consequences of 60 min experimental testicular torsion, followed by 240 min of reperfusion, were examined. Using fluorescence intravital microscopy, changes in red blood cell velocity in post-capillary venules and rolling as well as adhesion of leukocytes in the postcapillary venules were examined before the torsion and every hour during the reperfusion period. Sildenafil was given 10 min prior to reperfusion (iv 0.7 mg/kg, n = 6), while control animals received saline vehicle (n = 5). The characteristic flow motion disappeared in the affected testicular during the torsion. Red blood cell velocity values were dramatically decreased (by > 50%) and both rolling and adhesion of leukocytes increased during the reperfusion phase. Sildenafil treatment resulted in significantly higher red blood cell velocity values during the entire reperfusion period, but exerted only a temporary positive effect on the plost-ischaemic leukocyte-endothelial interactions. Intraoperative administration of sildenafil during surgical detorsion may provide marked testicular microperfusion benefits, but failed to influence the overall leukocyte-driven microcirculatory inflammatory reactions.

Sildenafil Prevents Apoptosis of Human First-Trimester Trophoblast Cells Exposed to Oxidative Stress

PubMed Central

Bolnick, Jay M.; Kilburn, Brian A.; Bolnick, Alan D.; Diamond, Michael P.; Singh, Manvinder; Hertz, Michael; Dai, Jing

2015-01-01

Human first-trimester trophoblast cells proliferate at low O2, but survival is compromised by oxidative stress, leading to uteroplacental insufficiency. The vasoactive drug, sildenafil citrate (Viagra, Sigma, St Louis, Missouri), has proven useful in reducing adverse pregnancy outcomes. An important biological function of this pharmaceutical is its action as an inhibitor of cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 activity, which suggests that it could have beneficial effects on trophoblast survival. To investigate whether sildenafil can prevent trophoblast cell death, human first-trimester villous explants and the HTR-8/SVneo cytotrophoblast cell line were exposed to hypoxia and reoxygenation (H/R) to generate oxidative stress, which induces apoptosis. Apoptosis was optimally inhibited during H/R by 350 ng/mL sildenafil. Sildenafil-mediated survival was reversed by l-NG-nitro-l-arginine methyl ester hydrochloride or cGMP antagonist, indicating a dependence on both nitric oxide (NO) and cGMP. Indeed, either a cGMP agonist or an NO generator was cytoprotective independent of sildenafil. These findings suggest a novel intervention route for patients with recurrent pregnancy loss or obstetrical placental disorders. PMID:25431453

Extemporaneous sildenafil citrate oral suspensions for the treatment of pulmonary hypertension in children.

PubMed

Nahata, Milap C; Morosco, Richard S; Brady, Michael T

2006-02-01

The stability of sildenafil citrate 2.5 mg/mL in two extemporaneously prepared oral suspensions stored at 4 and 25 degrees C was studied. Thirty 25-mg tablets of sildenafil citrate were ground to powder, and the powder was combined with a 1:1 mixture of Ora-Sweet and Ora-Plus or a 1:1 mixture of methylcellulose 1% and Simple Syrup, NF, to produce two 2.5-mg/mL suspensions. Five plastic bottles of each suspension were stored in amber plastic prescription bottles at 4 or 25 degrees C. Samples were collected on days 0, 7, 14, 28, 42, 56, 70, and 91 for analysis of sildenafil content by high-performance liquid chromatography; pH was also measured. Samples were visually observed against black and white backgrounds. The mean concentration of sildenafil citrate exceeded 98% of the initial concentration in all samples at both temperatures throughout the 91-day study period. No changes in pH, odor, or physical appearance were observed. Sildenafil citrate 2.5 mg/mL in two extemporaneously compounded oral suspensions was stable for 91 days in plastic prescription bottles at 4 and 25 degrees C.

Concentration-dependent Sildenafil citrate (Viagra) effects on ROS production, energy status, and human sperm function.

PubMed

Sousa, Maria Inês; Amaral, Sandra; Tavares, Renata Santos; Paiva, Carla; Ramalho-Santos, João

2014-04-01

Literature regarding the effects of sildenafil citrate on sperm function remains controversial. In the present study, we specifically wanted to determine if mitochondrial dysfunction, namely membrane potential, reactive oxygen species production, and changes in energy content, are involved in in vitro sildenafil-induced alterations of human sperm function. Sperm samples of healthy men were incubated in the presence of 0.03, 0.3, and 3 μM sildenafil citrate in a phosphate buffered saline (PBS)-based medium for 2, 3, 12, and 24 hours. Sperm motility and viability were evaluated and mitochondrial function, i.e., mitochondrial membrane potential and mitochondrial superoxide production were assessed using flow-cytometry. Additionally, adenosine triphosphate (ATP) levels were determined by high performance liquid chromatography (HPLC) analysis. Results show a decrease in sperm motility correlated with the level of mitochondria-generated superoxide, without a visible effect on mitochondrial membrane potential or viability upon exposure to sildenafil. The effect on both motility and superoxide production was higher for the intermediate concentration of sildenafil (0.3 µM) indicating that the in vitro effects of sildenafil on human sperm do not vary linearly with drug concentration. Adenosine triphosphate levels also decreased following sildenafil exposure, but this decrease was only detected after a decrease in motility was already evident. These results suggest that along with the level of ATP and mitochondrial function other factors are involved in the early sildenafil-mediated decline in sperm motility. However, the further decrease in ATP levels and increase in mitochondria-generated reactive oxygen species after 24 hours of exposure might further contribute towards declining sperm motility.

Sildenafil therapy in thalassemia patients with Doppler-defined risk of pulmonary hypertension

PubMed Central

Morris, Claudia R.; Kim, Hae-Young; Wood, John; Porter, John B.; Klings, Elizabeth S.; Trachtenberg, Felicia L.; Sweeters, Nancy; Olivieri, Nancy F.; Kwiatkowski, Janet L.; Virzi, Lisa; Singer, Sylvia T.; Taher, Ali; Neufeld, Ellis J.; Thompson, Alexis A.; Sachdev, Vandana; Larkin, Sandra; Suh, Jung H.; Kuypers, Frans A.; Vichinsky, Elliott P.

2013-01-01

Pulmonary hypertension is a common but often overlooked complication associated with thalassemia syndromes. There are limited data on the safety and efficacy of selective pulmonary vasodilators in this at-risk population. We, therefore, designed a 12-week, open-label, phase 1/2, pilot-scale, proof-of-principle trial of sildenafil therapy in 10 patients with β-thalassemia and at increased risk of pulmonary hypertension based on an elevated tricuspid regurgitant jet velocity >2.5 m/s on Doppler-echocardiography. Variables compared at baseline and after 12 weeks of sildenafil treatment included Doppler-echocardiographic parameters, 6-minute walked distance, Borg Dyspnea Score, New York Heart Association functional class, pulmonary function, and laboratory parameters. Treatment with sildenafil resulted in a significant decrease in tricuspid regurgitant jet velocity by 13.3% (3.0±0.7 versus 2.6±0.5 m/s, P=0.04), improved left ventricular end systolic/diastolic volume, and a trend towards a improved New York Heart Association functional class. No significant change in 6-minute walked distance was noted. Sildenafil was well tolerated, although minor expected adverse events were commonly reported. The total dose of sildenafil (mg) was strongly correlated with percent change in nitric oxide metabolite concentration in the plasma (ρ=0.80, P=0.01). There were also significant increases in plasma and erythrocyte arginine concentrations. Our study suggests that sildenafil is safe and may improve pulmonary hemodynamics in patients at risk of pulmonary hypertension; however, it was not demonstrated to improve the distance walked in 6 minutes. Clinical trials are needed to identify the best treatment strategy for pulmonary hypertension in patients with β-thalassemia. (clinicaltrials.gov identifier: NCT00872170) PMID:23585527

The effect of sildenafil on oesophageal motor function in healthy subjects and patients with nutcracker oesophagus.

PubMed

Lee, J I; Park, H; Kim, J H; Lee, S I; Conklin, J L

2003-12-01

Type 5 phosphodiesterase terminates the action of nitric oxide (NO) induced 3',5'-cyclic monophosphate (cGMP). Sildenafil inhibits this phosphodiesterase, increases cellular cGMP concentrations and enhances NO-induced smooth muscle relaxation. We investigated the effect of sildenafil on the oesophageal motor function of healthy subjects and patients with nutcracker oesophagus. Eight healthy volunteers and nine patients with nutcracker oesophagus participated in this study. The participants underwent oesophageal manometries on two separate days after either 20 mL of distilled water or 0.8 mg kg-1 sildenafil dissolved in 20 mL of water was infused into the stomach. Lower oesophageal sphincter (LOS) resting pressure, the duration of LOS relaxation and the amplitudes of oesophageal pressure waves were examined before, and 7.5, 15, 30 and 60 min after either placebo or sildenafil. In both healthy subjects and patients with nutcracker oesophagus, sildenafil decreased resting LOS pressure and the amplitude of peristaltic pressure waves at 3, 8 and 13 cm above LOS. Sildenafil also prolonged the duration of LOS relaxation. It had no effect on the velocity of peristalsis or the amplitude of peristaltic pressure waves 18 cm above LOS. Sildenafil may be considered as an alternative treatment in nutcracker oesophagus although there are several limitations to be overcome.

Tadalafil for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a review of clinical data in Asian men and an update on the mechanism of action

PubMed Central

Igawa, Yasuhiko; Takeda, Masayuki; Yamaguchi, Takafumi; Murakami, Masahiro; Viktrup, Lars

2015-01-01

Tadalafil, a phosphodiesterase type 5 (PDE5) inhibitor, is approved worldwide for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH-LUTS). The purpose of this narrative review is to summarize the clinical data on tadalafil 5 mg once-daily, primarily focusing on Asian men with BPH-LUTS, and to update the current understanding of the mechanism of action underlying PDE5 inhibition. Findings from studies have demonstrated that PDE5 is highly expressed in the lower urinary tract and supporting vasculature, and that PDE5 inhibition potentially decreases smooth muscle cell proliferation in the prostate, relaxes smooth muscle in the prostate, bladder neck and supporting vasculature, increases blood perfusion to the lower urinary tract, and modulates bladder afferent nerve activity. A total of 11 larger, 12-week, double-blind, randomized, placebo-controlled studies of tadalafil, including four Asian studies, have been conducted globally, enrolling >3000 men with BPH-LUTS. In addition, two long-term (42- and 52-week) studies enrolled 394 Japanese and 428 North American men, respectively, with BPH-LUTS. Overall, tadalafil 5 mg once-daily resulted in significant improvements in the change from baseline to endpoint in total International Prostate Symptom Scores (IPSS), IPSS storage and voiding subscores, and IPSS quality of life index compared with placebo. Tadalafil was well tolerated and had a favorable safety profile. These findings support tadalafil 5 mg once-daily for treating men, including Asian men, with BPH-LUTS. PMID:26425140

Sildenafil citrate for erectile dysfunction in patients with multiple sclerosis.

PubMed

Xiao, Yousheng; Wang, Jin; Luo, Hongye

2012-04-18

Erectile dysfunction (ED) is a common sexual disease in male patients with multiple sclerosis (MS). Sildenafil citrate is considered as an effective drug in the treatment of male ED in the general population, but it has not been systematically reviewed in patients with MS. To assess the efficacy and safety of sildenafil citrate for ED in patients with MS. We searched the Cochrane (November 2011), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 4 of 4, 2011), MEDLINE (PubMed) (January 1966 to November 2011), EMBASE (January 1974 to November 2011) and the China Biological Medicine Database (CBM) (1979 to November 2011). We searched trials registers and conference proceedings and contacted pharmaceutical company and authors of included studies for additional data. There were no language restrictions. Randomised controlled trials comparing sildenafil citrate with placebo or no treatment for ED in patients with MS. Two review authors independently selected articles for inclusion, extracted data and assessed trial quality. Disagreements were resolved by discussion between review authors. Authors of included studies were contacted for additional information. Results were presented as relative risks (RR) or mean differences (MD) with 95% confidence intervals (CI). Two randomised controlled trials involving a total of 420 patients were identified. Both trials investigated the short-term efficacy and safety of sildenafil citrate for ED in patients with MS. Patients taking sildenafil citrate were more likely to improve their ability to achieve and maintain an erection measured by International Index of Erectile Function and achieve vaginal penetration ( (RR 1.28, 95%CI 0.92 to 1.78) and complete intercourse measured by Sexual Encounter Profile diary (RR RR 1.38, 95%CI 1.00 to 1.90). and receive A global well respond measured by Global Assessment Question (RR 2.72, 95%CI 1.40 to 5.28) was reported. One trial showed sildenafil citrate is

Physicians' response to sexual dysfunction presented by a younger vs. An older adult.

PubMed

Gewirtz-Meydan, Ateret; Ayalon, Liat

2017-12-01

The aim of this study is to determine whether physicians have an age bias regarding sexual dysfunction presented by older vs. younger patients in terms of attributed diagnosis, etiology, proposed treatment and perceived prognosis. An on-line survey consisting of one of two, randomly administered, case vignettes, which differed only by the age of the patient (28 or 78). In both cases, the patient was described as suffering from occasional erectile dysfunction with a clear psychosocial indication. A total of 236 physicians responded to the survey. Overall, 110 physicians received an "old" vignette and 126 physicians received a "young" vignette. Even though both cases presented with a clear psychosocial etiology, the "older" vignette was more likely to be diagnosed with erectile dysfunction whereas the "younger" vignette was more likely to be diagnosed with performance anxiety. The "older" vignette's dysfunction was more likely to be attributed to hormonal changes, health problems and decreased sexual desire. Physicians were more likely to recommend testosterone replacement therapy (TRT) and PDE5 inhibitors (PDE5i; such as Sildenafil; Vardenafil; Tadalafil) as well as a referral to urology to the "older" vignette. In contrast, the "younger" vignette was more often referred to a sexologist and received a more positive prognosis than the older patient. This study demonstrates an age bias among physicians regarding sexuality in later life. Of particular note is the tendency to prescribe PDE5i to the older patient, despite the clear psychosocial indication presented in the case vignette. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Screening of synthetic PDE-5 inhibitors and their analogues as adulterants: analytical techniques and challenges.

PubMed

Patel, Dhavalkumar Narendrabhai; Li, Lin; Kee, Chee-Leong; Ge, Xiaowei; Low, Min-Yong; Koh, Hwee-Ling

2014-01-01

The popularity of phosphodiesterase type 5 (PDE-5) enzyme inhibitors for the treatment of erectile dysfunction has led to the increase in prevalence of illicit sexual performance enhancement products. PDE-5 inhibitors, namely sildenafil, tadalafil and vardenafil, and their unapproved designer analogues are being increasingly used as adulterants in the herbal products and health supplements marketed for sexual performance enhancement. To date, more than 50 unapproved analogues of prescription PDE-5 inhibitors were found as adulterants in the literature. To avoid detection of such adulteration by standard screening protocols, the perpetrators of such illegal products are investing time and resources to synthesize exotic analogues and devise novel means for adulteration. A comprehensive review of conventional and advance analytical techniques to detect and characterize the adulterants is presented. The rapid identification and structural elucidation of unknown analogues as adulterants is greatly enhanced by the wide myriad of analytical techniques employed, including high performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS), liquid chromatography mass-spectrometry (LC-MS), nuclear magnetic resonance (NMR) spectroscopy, vibrational spectroscopy, liquid chromatography-Fourier transform ion cyclotron resonance-mass spectrometry (LC-FT-ICR-MS), liquid chromatograph-hybrid triple quadrupole linear ion trap mass spectrometer with information dependent acquisition, ultra high performance liquid chromatography-time of flight-mass spectrometry (UHPLC-TOF-MS), ion mobility spectroscopy (IMS) and immunoassay methods. The many challenges in detecting and characterizing such adulterants, and the need for concerted effort to curb adulteration in order to safe guard public safety and interest are discussed. Copyright © 2013 Elsevier B.V. All rights reserved.

Efficacy and safety of oral sildenafil in children with Down syndrome and pulmonary hypertension.

PubMed

Beghetti, Maurice; Rudzinski, Andrzej; Zhang, Min

2017-07-04

Despite the increased risk for pulmonary hypertension in children with Down syndrome, the response to treatment with targeted therapies for pulmonary hypertension in these patients is not well characterized. The Sildenafil in Treatment-naive children, Aged 1-17 years, with pulmonary arterial hypertension (STARTS-1) trial was a dose-ranging study of the short-term efficacy and safety of oral sildenafil in children with pulmonary arterial hypertension. We assessed the safety and efficacy of oral sildenafil in children with Down syndrome and pulmonary arterial hypertension. This was a post-hoc analysis of children with Down syndrome and pulmonary arterial hypertension enrolled in the STARTS-1 trial. Mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance index (PVRI), and cardiac index (CI) were assessed at baseline and following 16 weeks of treatment with sildenafil. Of 234 patients randomized and treated in the STARTS-1 trial, 48 (20.5%) had Down syndrome. Although sildenafil produced dose-related reductions in PVRI and mPAP, compared with placebo, in non-Down syndrome patients and children developmentally able to exercise, this was not satisfactorily marked in patients with Down syndrome. The dose-related reductions in PVRI, compared with placebo, occurred in all subgroups, with the exception of the Down syndrome subgroup. Sildenafil appeared to be well tolerated in the Down syndrome subpopulation and the most frequently reported AEs were similar to those reported for the entire STARTS-1 population. Sildenafil treatment for 16 weeks had no effect on PVRI or mPAP in children with Down syndrome and pulmonary arterial hypertension. The results suggest that children with Down syndrome may be less responsive to sildenafil for pulmonary arterial hypertension, but the incomplete work-up for the etiology of pulmonary arterial hypertension may have introduced a potential bias. Study received, September 8, 2005 (retrospectively registered); Study start

Sildenafil Preserves Exercise Capacity in Patients With Idiopathic Pulmonary Fibrosis and Right-sided Ventricular Dysfunction

PubMed Central

Bach, David S.; Hagan, Peter G.; Yow, Eric; Flaherty, Kevin R.; Toews, Galen B.; Anstrom, Kevin J.; Martinez, Fernando J.

2013-01-01

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with pulmonary vasculopathy. Objective: The purpose of this study was to determine whether sildenafil improves 6-min walk distance (6MWD) in subjects with IPF and right ventricular dysfunction. Methods: The IPFnet, a network of IPF research centers in the United States, conducted a randomized trial examining the effect of sildenafil on 6MWD in patients with advanced IPF, defined by carbon monoxide diffusing capacity < 35% predicted. A substudy examined 119 of 180 randomized subjects where echocardiograms were available for independent review by two cardiologists. Right ventricular (RV) hypertrophy (RVH), right ventricular systolic dysfunction (RVSD), and right ventricular systolic pressure (RVSP) were assessed. Multivariable linear regression models estimated the relationship between RV abnormality, sildenafil treatment, and changes in 6MWD, St. George’s Respiratory Questionnaire (SGRQ), the EuroQol instrument, and SF-36 Health Survey (SF-36) from enrollment to 12 weeks. Results: The prevalence of RVH and RVSD were 12.8% and 18.6%, respectively. RVSP was measurable in 71 of 119 (60%) subjects; mean RVSP was 42.5 mm Hg. In the subgroup of subjects with RVSD, subjects treated with sildenafil experienced less decrement in 6MWD (99.3 m; P = .01) and greater improvement in SGRQ (13.4 points; P = .005) and EuroQol visual analog scores (17.9 points; P = .04) than subjects receiving placebo. In the subgroup with RVH, sildenafil was not associated with change in 6MWD (P = .13), but was associated with greater relative improvement in SGRQ (14.8 points; P = .02) vs subjects receiving placebo. Sildenafil treatment in those with RVSD and RVH was not associated with change in SF-36. Conclusions: Sildenafil treatment in IPF with RVSD results in better preservation of exercise capacity as compared with placebo. Sildenafil also improves quality of life in subjects with RVH and RVSD. PMID:23732584

Sexual asthenia: Tradamixina versus Tadalafil 5 mg daily

PubMed Central

2012-01-01

Background Reduced libido is widely considered the most prominent symptomatic reflection of low testosterone (T) levels in men. Testosterone deficiency (TD) afflicts approximately 30% of men aged 40-79 years. This study seeks to evaluate the effect of a new natural compound “tradamixina “in order to improve male sexual function in elderly men, particularly libido and possible erectile dysfunction, versus administration of tadalafil 5 mg daily. Methods Seventy patients (67.3± 3.7 years) with stable marital relations and affected by reduced libido, with or without erectile dysfunction were recruited. They were randomly separated in 2 groups A-B of 35. Group A was administered twice a day a new compound “Tradamixina” (150 mg of Alga Ecklonia Bicyclis, 396 mg of Tribulus Terrestris and 144 mg of D-Glucosamine and N-Acetyl-D-Glucosamine) for two months, while Group B was administered tadalafil 5 mg daily, for two months. At visit and after 60 days of treatment patients were evaluated by means of detailed medical and sexual history, clinical examination, laboratory investigations (Total and Free T), instrumental examination (NPTR- nocturnal penile tumescence and rigidity test- with Rigiscan). Patients completed a self-administered IIEF questionnaire (The international index of erectile function) and SQoLM questionnaire (Sexual quality of life Questionnarie-Male). The results pre and post treatment were compared by Student t test (p<0.005). Results After 2 months of treatment in group A serum TT levels (230±18 ng/dl vs 671±14 ng/dl ) and FT levels(56± 2.4 pg/ml vs 120± 3.9pg/ml) increased, while in group B serum TT levels (245±12 ng/dl vs 247±15 ng/dl ) and FT levels(53± 0.3 pg/ml vs 55± 0.5pg/ml) increased not statistically significant. The patient’s numbers with negative NPTR improved after treatment in group A and B (15 vs 18 and 13 vs 25 respectively). The IIEF total score in group A increased after treatment with tradamixina (15±1.5 vs 29.77±1

Treatment of pulmonary arterial hypertension using extemporaneous formulation of sildenafil in Mexican children.

PubMed

Juárez Olguín, Hugo; Camacho Reyes, Laura; Roldan Arce, Arturo; Calderón Guzmán, David

2015-06-01

Pulmonary arterial hypertension (PAH) is a sickness with high rate of mortality that consists of elevation in pressure of the vessels through which blood flows to the lung. Sildenafil is a therapeutic option for the treatment of PAH in children for the fact that it relaxes the blood vessels and thereby improves pulmonary blood flow. The aim was to analyze the clinical behavior of an extemporaneous formulation of sildenafil as a therapeutic option in children with PAH, twelve children with PAH were studied. The ages and weights of the children ranged from 5 to 15 years and from 13 to 27 kg. All patients received a capsule of 1 mg/kg of sildenafil prepared as extemporaneous formulation in the pharmacology laboratory. Blood levels of sildenafil were analyzed in order to evaluate its availability of developed formulation. Management has derived from physiopathological knowledge and clinical presentations of patients. The mean maximum concentration was 550 ng/ml which is greater than levels reported in adults. Moreover, a therapeutic monitoring of sildenafil was carried out in order to establish an adequate therapeutic range for children and to show that dosages prepared extemporaneously meet the therapeutic needs for the management of PAH. With an average follow-up of once every 2 months, it was found that the evolution of the patients was favorable and without adverse effects that could put their life at risk. The management of PAH with sildenafil prepared as extemporaneous formulation might be considered as a good therapeutic option.

Molecular characterization of microbial population dynamics during sildenafil citrate degradation.

PubMed

De Felice, Bruna; Argenziano, Carolina; Guida, Marco; Trifuoggi, Marco; Russo, Francesca; Condorelli, Valerio; Inglese, Mafalda

2009-02-01

Little is known about pharmaceutical and personal care products pollutants (PPCPs), but there is a growing interest in how they might impact the environment and microbial communities. The widespread use of Viagra (sildenafil citrate) has attracted great attention because of the high usage rate, the unpredictable disposal and the unknown potential effects on wildlife and the environment. Until now information regarding the impact of Viagra on microbial community in water environment has not been reported. In this research, for the first time, the genetic profile of the microbial community, developing in a Viagra polluted water environment, was evaluated by means of the 16S and 18S rRNA genes, for bacteria and fungi, respectively, amplified by polymerase chain reaction (PCR) and separated using the denaturing gradient gel electrophoresis (DGGE) technique. The DGGE results revealed a complex microbial community structure with most of the population persisting throughout the experimental period. DNA sequences from bands observed in the different denaturing gradient gel electrophoresis profiles exhibited the highest degree of identity to uncultured bacteria and fungi found previously mainly in polluted environmental and treating bioreactors. Biotransformation ability of sildenafil citrate by the microbial pool was studied and the capability of these microorganisms to detoxify a polluted water ecosystem was assessed. The bacterial and fungal population was able to degrade sildenafil citrate entirely. Additionally, assays conducted on Daphnia magna, algal growth inhibition assay and cell viability determination on HepG2 human cells showed that biotransformation products obtained from the bacterial growth was not toxic. The higher removal efficiency for sildenafil citrate and the lack of toxicity by the biotransformation products obtained showed that the microbial community identified here represented a composite population that might have biotechnological relevance to

Sildenafil ameliorates left ventricular T-tubule remodeling in a pressure overload-induced murine heart failure model

PubMed Central

Huang, Chun-kai; Chen, Bi-yi; Guo, Ang; Chen, Rong; Zhu, Yan-qi; Kutschke, William; Hong, Jiang; Song, Long-sheng

2016-01-01

Aim: Sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, has been shown to exert beneficial effects in heart failure. The purpose of this study was to test whether sildenafil suppressed transverse-tubule (T-tubule) remodeling in left ventricular (LV) failure and thereby providing the therapeutic benefits. Methods: A pressure overload-induced murine heart failure model was established in mice by thoracic aortic banding (TAB). One day after TAB, the mice received sildenafil (100 mg·kg−1·d−1, sc) or saline for 5 weeks. At the end of treatment, echocardiography was used to examine LV function. Then the intact hearts were dissected out and placed in Langendorff-perfusion chamber for in situ confocal imaging of T-tubule ultrastructure from epicardial myocytes. Results: TAB surgery resulted in heart failure accompanied by remarkable T-tubule remodeling. Sildenafil treatment significantly attenuated TAB-induced cardiac hypertrophy and congestive heart failure, improved LV contractile function, and preserved T-tubule integrity in LV cardiomyocytes. But sildenafil treatment did not significantly affect the chamber dilation. The integrity of LV T-tubule structure was correlated with cardiac hypertrophy (R2=0.74, P<0.01) and global LV function (R2=0.47, P<0.01). Conclusion: Sildenafil effectively ameliorates LV T-tubule remodeling in TAB mice, revealing a novel mechanism underlying the therapeutic benefits of sildenafil in heart failure. PMID:26972492

Lower self-reported depression in patients with erectile dysfunction after treatment with sildenafil.

PubMed

Müller, M J; Benkert, O

2001-10-01

Depressive symptoms in men with erectile dysfunction (ED) may improve under successful ED treatment. Self-reported depressive symptoms were compared in men with ED after sildenafil treatment to a group of untreated patients. In an open study, self-reported depressive symptoms of 54 men after successful treatment with sildenafil (>4 weeks) and 51 men awaiting ED treatment were investigated with the Center of Epidemiologic Studies-Depression Scale (CES-D). CES-D items were subjected to an exploratory factor analysis and group differences in CES-D items and factors were analyzed. Groups were comparable with respect to demographic characteristics and illness duration. CES-D total scores were lower in the group treated with sildenafil. Substantial differences were found in favor of the group treated with sildenafil, particularly in scores on a "positive affect" factor. The findings emphasize the relevance of depression associated with ED and the importance of effective ED treatment. Although depression was generally low in this sample, hedonistic aspects were substantially enhanced in the group of ED patients after sildenafil treatment. The open and cross-sectional study design does not permit causal inference. Selection bias and motivational aspects to participate in the study can not completely be ruled out.

Tadalafil once daily in the treatment of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) in men without erectile dysfunction.

PubMed

Brock, Gerald; Broderick, Gregory; Roehrborn, Claus G; Xu, Lei; Wong, David; Viktrup, Lars

2013-11-01

To assess the safety and efficacy of tadalafil once daily on lower urinary tract symptoms suggestive of clinical benign prostatic hyperplasia (BPH-LUTS) in men without erectile dysfunction (ED). To compare these with effects in men with ED. After a 4-week washout period and 4-week placebo run-in period, 1089 men without ED (n = 338) and with ED (n = 751) were randomly assigned to placebo or tadalafil 5 mg once daily for 12 weeks in three global clinical studies with similar designs. In the pooled dataset, post hoc analyses of covariance assessed the impact and severity of BPH-LUTS using the International Prostate Symptom Score (IPSS) and the BPH Impact Index (BII) and IPSS quality-of-life (IPSS-QoL) subscores. Safety was assessed using treatment-emergent adverse events. The treatment-by-ED-status interaction was used to assess efficacy differences between the with/without ED subgroups. Men without ED were similar in BPH-LUTS severity/previous therapy to men with ED. Tadalafil significantly reduced BPH-LUTS from baseline when compared with placebo in men without ED (IPSS -5.4 vs -3.3, P < 0.01; IPSS voiding subscore -3.5 vs -2.0, P < 0.01; IPSS storage subscore -1.9 vs -1.3, P < 0.05). Tadalafil also significantly improved quality of life from baseline when compared with placebo in men without ED (IPSS-QoL -1.0 vs -0.7, BII -1.4 vs -1.0; both P < 0.05). Between-ED-subgroup interactions were not significant (all P > 0.68). Tadalafil was safe and well tolerated. Tadalafil 5 mg once daily improved BPH-LUTS in men without ED by a magnitude similar to that observed in men with ED. The adverse event profile in men without ED was consistent with that observed in men with ED. © 2013 The Authors. BJU International © 2013 BJU International.

Effect of daily sildenafil on patients with absent nocturnal erections due to pelvic fracture urethral disruption: a single-centre experience.

PubMed

Peng, J; Zhang, Z; Gao, B; Yuan, Y; Cui, W; Tang, Y; Song, W; Xin, Z

2016-12-01

Erectile dysfunction (ED) is a common sequel of pelvic fracture urethral disruption. Those patients with nocturnal erections may respond favourably to sildenafil; however, little is known about the response to sildenafil in patients with absent nocturnal erections. The aim was to evaluate the response to the treatment of sildenafil 50 mg taken once daily in the patients with absent nocturnal erections. From January 2008 to December 2011, a total of 28 patients with absent nocturnal erections were evaluated. We recorded nocturnal penile tumescence and rigidity with an erectometer. If nocturnal erections were absent for three nights, patients were administrated sildenafil 100 mg at bedtime and tested again at the fourth night. Penile duplex ultrasound with intracavernous injection was performed to define the cause of ED. All patients received a daily dose of sildenafil 50 mg for 12 weeks. Response to sildenafil treatment was defined as sustained erections allowing vaginal penetration and intercourse. Twenty-three (78%) patients completed the daily sildenafil treatment, and follow-up was available. The nocturnal erections at the fourth night in 13 patients (46.4%) were improved. About 61.5% (8/13) reported effective response to daily sildenafil. The improvement of nocturnal erections induced by sildenafil taken at bedtime might predict the response to sildenafil taken daily. © 2016 Blackwell Verlag GmbH.

Sildenafil counteracts the inhibitory effect of social subordination on competitive aggression and sexual motivation in male mice.

PubMed

Dadomo, Harold; Volpi, Riccardo; Ferrari, Massimiliano; Vignali, Alessandro; Bartolomucci, Alessandro; Palanza, Paola; Parmigiani, Stefano

2011-01-01

The effects of chronic intra-peritoneal administration of 10 mg/kg (t.i.w., for 5 weeks) of sildenafil on competitive aggression, sexual behaviour and body weight gain was tested in CD1 subordinate male mice in two experimental contexts: 1) "low levels of aggression", i.e. housing in dyads of siblings 2) "high levels of aggression", i.e. exposure to a model of chronic psychosocial stress with an unfamiliar mice. Subordinate mice in both experimental contexts were injected with sildenafil or saline. After 2 weeks of sildenafil administration, a subgroup of subordinates exposed to "high levels of aggression" began to counterattack their dominant counterparts at higher rates than saline-injected subordinates. This effect was essentially similar but faster in subordinates subjected to "low levels of aggression". As far as sexual behaviour is concerned, in both experimental contexts, sildenafil-injected subordinated mice showed significant lower latencies to mount a proceptive female when compared to saline-injected subjects. Furthermore, in the "high levels of aggression" context, Sildenafil reduced stress-induced body weight gain. Sildenafil showed no effects in individually housed males serving as controls. In conclusion, chronic Sildenafil treatment counteracts the inhibitory effects of social subordination on male competitive aggression, sexual behaviour and body weight gain. Overall our data suggests that sildenafil could be acting in the central nervous system to modulate sexual and agonistic motivation. Copyright © 2010 Elsevier B.V. All rights reserved.

Oral sildenafil citrate (viagra) for erectile dysfunction: a systematic review and meta-analysis of harms.

PubMed

Tsertsvadze, Alexander; Yazdi, Fatemeh; Fink, Howard A; MacDonald, Roderick; Wilt, Timothy J; Bella, Anthony J; Ansari, Mohammed T; Garritty, Chantelle; Soares-Weiser, Karla; Daniel, Raymond; Sampson, Margaret; Moher, David

2009-10-01

To summarize and compare evidence on harms in sildenafil- and placebo-treated men with erectile dysfunction (ED) in a systematic review and meta-analysis. Randomized placebo-controlled trials (RCTs) were identified using an electronic search in MEDLINE, EMBASE, PsycINFO, SCOPUS, and Cochrane CENTRAL. The rates of any adverse events (AEs), most commonly reported AEs, withdrawals because of adverse events, and serious adverse events were ascertained and compared between sildenafil and placebo groups. The results of men with ED were stratified by clinical condition(s). Statistical heterogeneity was explored. Meta-analyses based on random-effects model were also performed. A total of 49 RCTs were included. Sildenafil-treated men had a higher risk for all-cause AEs (RR = 1.56, 95% CI: 1.38, 1.76), headache, flushing, dyspepsia, and visual disturbances compared with placebo-treated men. The magnitude of excess risk was greater in fixed- than in flexible-dose trials. The rates of serious adverse events and withdrawals because of adverse events did not differ in sildenafil vs placebo groups. A higher dose of sildenafil corresponded to a greater risk of AEs. The increased risk of harms was observed within and across clinically defined specific groups of patients. There was a lack of RCTs reporting long-term (>6 months) harms data. In short-term trials, men with ED randomized to sildenafil had an increased risk of all-cause any AEs, headache, flushing, dyspepsia, and visual disturbances. The exploration of different modes of dose optimization of sildenafil may be warranted.

Dose-dependent protective effect of sildenafil citrate on testicular injury after torsion/detorsion in rats.

PubMed

Yıldız, H; Durmus, A S; Şimşek, H; Yaman, M

2012-05-01

This experiment was designed to investigate the effect of sildenafil citrate on testicular injury after unilateral testicular torsion/detorsion (T/D). Thirty-seven adult male Wistar albino rats were divided into four groups: sham operated group (group 1), T/D+ saline (group 2), T/D+ 0.7 mg sildenafil citrate (group 3) and T/D+ 1.4 mg sildenafil citrate (group 4). Testicular torsion was created by rotating the right testis 720° in a clockwise direction for 2 h in other groups, except for group 1, which was served as sham group. The level of GSH (P < 0.05) in the testis in the group 2 were significantly lower (P < 0.05) and the levels of MDA and NO (P < 0.01 for both) in the testis were significantly higher when compared with those of the group 1. Administration of low dose sildenafil citrate prevented the increases in MDA and NO levels and decreases in GSH values induced by testicular torsion. However, administration of high dose sildenafil citrate did not have any effect on these testicular tissue parameters (P > 0.05). Also, mean values of seminiferous tubules diameters, germinal cell layer thicknesses and mean testicular biopsy score were significantly better in group 3 than groups 2 and 4. These results suggest that T/D injury occurred in testis after unilateral testicular T/D and that administration of low dose sildenafil citrate before detorsion prevents ischemia/reperfusion cellular damage in testicular torsion. Sildenafil citrate probably acts through reduction of reactive oxygen species and support antioxidant enzyme systems. © 2011 Blackwell Verlag GmbH.

Effect of sildenafil citrate (Viagra®) on trace element concentration in serum and brain of rats.

PubMed

Fayed, Abdel-Hasseb A; Gad, Shereen B

2011-12-01

As a vasodilator with good hemodynamic effects, sildenafil has been successfully used in the treatment of patients with pulmonary hypertension and cardiovascular diseases. By selectively inhibiting phosphodiestrase type 5 (PDE-5) and thus effectively reducing the breakdown of c GMP, sildenafil administration can markedly improve the erectile dysfunction. Sildenafil also elevates localized cerebral blood flow in rat brain. The objective of the present study was to investigate the effect of sildenafil on the level of trace elements (Zinc (Zn), copper (Cu), iron (Fe), selenium (Se), cobalt (Co), and chromium (Cr)) in blood and brain of rats. Sixteen male albino rats weighing 180-200 g were divided into two groups (8 rats/group). Sildenafil (Viagra, Pfizer Inc.) was dissolved in saline and administered at a dose of 10mg/kg i.p. (0.5 ml volume) to rats in the treated group every 72 h for 12 injections. Rats in the control group were administered the same volume of saline as in treated group. All rats were sacrificed 24h after the last injection. Blood samples were collected and serum was separated and stored at -20°C. Brains were dissected and stored frozen until analysis. Trace elements concentrations were determined by flame emission atomic absorption spectrophotometer. Results showed that sildenafil injection significantly (P<0.05) increased serum and brain Se and Cu concentrations. Moreover, sildenafil increased the Cr concentration in the brain tissue. It was concluded that sildenafil citrate administration increased serum Se and Cu as well as, increased brain Se, Cu, and Cr concentrations in rats. Copyright © 2011 Elsevier GmbH. All rights reserved.

A systematic review assessing the economic impact of sildenafil citrate (Viagra) in the treatment of erectile dysfunction.

PubMed

Martin, Amber L; Huelin, Rachel; Wilson, David; Foster, Talia S; Mould, Joaquin F

2013-05-01

Sildenafil was the first oral phosphodiesterase type 5 (PDE5) inhibitor introduced as primary therapy for erectile dysfunction (ED). In the 7 years following its market launch, sildenafil was prescribed by more than 750,000 physicians to more than 23 million men worldwide. To date, few studies have evaluated the economic impact of sildenafil in treating ED. To evaluate the cost-effectiveness and impact of sildenafil on health care costs for patients with ED in multiple countries. Economic outcomes including cost, cost-effectiveness, cost of illness, cost consequence, resource use, productivity, work loss, and willingness to pay (WTP) were investigated. Using keywords related to economic outcomes and sildenafil, we systematically searched literature published between July 2001 and July 2011 using MEDLINE and EMBASE. Included articles pertained to costs, WTP, and economic evaluations. In the last 10 years, 12 studies assessed economic outcomes associated with sildenafil for ED. Most studies were conducted in the United States and the United Kingdom, with one study identified in Canada and one from Mexico. Six studies evaluated cost of illness, cost consequence, or cost of care, and four studies evaluated WTP or drug pricing by country in the United States and the United Kingdom. In the United States and the United Kingdom, costs to health care systems have increased with demand for treatment. Cost analyses suggested that sildenafil would lower direct costs compared with other PDE5 inhibitors. U.S. and U.K. studies found that patients exhibited WTP for sildenafil. The two cost-effectiveness models we identified examined ED sub-groups, those with spinal cord injury and those with diabetes or hypertension. These models indicated favorable cost-effectiveness profiles for sildenafil compared with other active-treatment options in both Mexico and Canada. The relative value of sildenafil vs. surgically implanted prosthetic devices and other PDE5 inhibitors, is underscored

The role of initial success rates and other factors in determining reliability of outcomes of phosphodiesterase inhibitor therapy for erectile dysfunction: a pooled analysis of 17 placebo-controlled trials of tadalafil for use as needed.

PubMed

Sontag, Angelina; Rosen, Raymond C; Litman, Heather J; Ni, Xiao; Araujo, Andre B

2013-02-01

Reliability of successful outcomes in men with erectile dysfunction (ED) on phosphodiesterase type 5 inhibitors is an important aspect of patient management. We examined reliability of successful outcomes in a large integrated dataset of randomized tadalafil trials. Success rates, time to success, subsequent success after first success, and probability of success were analyzed based on Sexual Encounter Profile questions 2 and 3. Data from 3,254 ED patients treated with tadalafil 10 mg (N = 510), 20 mg (N = 1,772), or placebo (N = 972) were pooled from 17 placebo-controlled studies. Tadalafil patients had significantly higher first-attempt success rates vs. placebo. This effect was consistent across most subgroups; however, patients with severe ED experienced a greater response to tadalafil than patients with mild-moderate ED. Approximately 80% of patients achieved successful penile insertion within two attempts with either tadalafil dose and successful intercourse within eight attempts for tadalafil 10 mg and four attempts for tadalafil 20 mg. However, approximately 70% of tadalafil-treated patients achieved successful intercourse even by the second attempt. Subsequent success rates were higher for patients with first-attempt success (81.5% for 10 mg and 86.1% for 20 mg vs. 66.2% for placebo, P < 0.001) vs. patients with later initial success (53.2% for 10 mg and 56.4% for 20 mg vs. 39.9% for placebo, P < 0.001). Among patients treated with tadalafil, intercourse success rates at early attempts were similar to rates at later attempts (i.e., attempts 5 and 10 vs. 25), although insertion success rates were significantly lower earlier in treatment. The findings affirm the reliability of successful outcomes with tadalafil treatment and that first-attempt success is a critical factor affecting subsequent outcomes. The results further show that even among men who did not succeed on first attempt, a substantial proportion will have successful outcomes if treatment is

Ameliorative effects of sildenafil and/or febuxostat on doxorubicin-induced nephrotoxicity in rats.

PubMed

Khames, Ali; Khalaf, Marwa M; Gad, Amany M; Abd El-Raouf, Ola M

2017-06-15

Sildenafil and febuxostat protect against doxorubicin-induced nephrotoxicity; however the exact mechanism remains to be elucidated. The effect of sildenafil and febuxostat on doxorubicin-induced nephrotoxicity in rats was studied. Male rats were subdivided into nine groups. The 1st group served as normal control, the 2nd group received dimethylsulfoxide 50% (DMSO), the 3rd group received doxorubicin (3.5mg/kg, i.p.), twice weekly for 3 weeks. The next 3 groups received sildenafil (5mg/kg; p.o.), febuxostat (10mg/kg; p.o.) and their combination, respectively daily for 21 days. The last 3 groups received doxorubicin in combination with sildenafil, febuxostat or their combination. Nephrotoxicity was evaluated histopathologically by light microscopy and biochemically through measuring the following parameters, Kidney function biomarkers [serum levels of urea, creatinine and uric acid], oxidative stress biomarkers [kidney contents of glutathione reduced (GSH) and malondialdehyde (MDA)], The apoptotic marker namely; caspase-3 in kidney tissue and the inflammatory mediator tumor necrosis factor alpha (TNF-α). doxorubicin-induced a significant elevation in nephrotoxicity markers, expression of caspase-3 and caused induction of inflammation and oxidative stress. Histological changes in the kidney was tubular necrosis. Sildenafil and/or febuxostat administration with doxorubicin caused a significant decrease in nephrotoxicity markers and inflammatory mediators, restoration of normal values of oxidative stress biomarkers and hampering the expression of renal caspase-3. They also ameliorate histological changes induced by doxorubicin. sildenafil and febuxostat are promising protective agents against doxorubicin-nephrotoxicity through improving biochemical, inflammatory, histopathological and immunohistochemical alterations induced by doxorubicin. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of Tadalafil Once-Daily or On-Demand vs Placebo on Return to Baseline Erectile Function After Bilateral Nerve-Sparing Radical Prostatectomy--Results from a Randomized Controlled Trial (REACTT).

PubMed

Mulhall, John P; Brock, Gerald; Oelke, Matthias; Fode, Mikkel; Probst, Kai A; Henneges, Carsten; d'Anzeo, Gianluca; Rossi, Andrea; Büttner, Hartwig

2016-04-01

The multicenter, randomized, double-blind, double-dummy, placebo-controlled REACTT trial suggested that treatment with tadalafil once daily (OaD) started early after bilateral nerve-sparing radical prostatectomy (nsRP) for prostate cancer may contribute to erectile function (EF)-recovery, which was predefined as achieving an International Index of Erectile Function (IIEF)-EF score ≥22. Here, we report descriptive post-hoc analyses, using the more strict definition for EF-recovery of returning back to the pre-surgery IIEF-EF-level ("back-to-baseline analysis"). REACTT included 422 men <68 years with adenocarcinoma of the prostate and preoperative IIEF-EF ≥22 who underwent nsRP at 50 centers from 9 European countries and Canada. Patients were randomized post-nsRP 1:1:1 to 9-month double-blind treatment (DBT) with tadalafil 5 mg OaD (n = 139), tadalafil 20 mg on-demand (pro-re-nata, PRN; n = 142), or placebo (n = 141), followed by 6-week drug-free washout (DFW) and 3-month open-label tadalafil OaD treatment (OLT). Proportion of patients returning to their preoperative IIEF-EF category (22-25 or ≥26) at the end of DBT, DFW, and OLT. Overall, 92.4% of patients had pre-surgery (baseline) IIEF-EF scores ≥26 (tadalafil OaD 94.2%, PRN 91.6%, placebo 91.5%), 7.4% had IIEF-EF 22-25. At the end of DBT, 22.3% of patients on tadalafil OaD had achieved "back-to-baseline" IIEF-EF, compared with 11.3% on tadalafil PRN and 7.8% on placebo. Of all 58 patients "back-to-baseline" at the end of DBT, only 1 PRN-group patient had started from a baseline IIEF-EF <26. The treatment-group difference at the end of DBT was not maintained after DFW. After 3 months of OLT with tadalafil OaD, the proportion of patients with "back-to-baseline" IIEF-EF had almost doubled in all 3 groups. Changing the definition for EF-recovery from IIEF-EF ≥22 to the more strict definition of "returning back-to-baseline IIEF-EF" had no major impact. Tadalafil OaD started early after nsRP improved

Efficacy of Tadalafil once daily versus Fesoterodine in the treatment of overactive bladder in older patients.

PubMed

Dell'Atti, L

2015-01-01

Several studies have suggested that phosphodiesterase type 5 inhibitors (5-PDEi) show a potential therapeutic use in the treatment of overactive bladder (OAB) and male lower urinary tract symptoms (LUTS). The aim of this study was to evaluating the efficacy on OAB symptoms, impact on quality of life and sexual function of tadalafil 5mg once daily in older patients versus fesoterodine 8 mg. 108 consecutive patients diagnosed with OAB were divided into 2 groups: Group A: 56 patients treated with tadalafil 5 mg once daily; Group B: 52 patients treated with fesoterodine 8 mg, both groups treated for a period of 12 weeks. Eligible patients were men aged ≥ 65 years with OAB symptoms, including urgency and increased frequency during a period of ≥ 1 year and urgency urinary incontinence during a period of ≥ 6 months before enrolment. Patients were asked to complete the 3-day voiding diary prior each scheduled visit at weeks 0, 4 and 12. During these visits, they were administered: Overactive Bladder Symptom Score (OABSS), International Prostate Symptoms Score (IPSS), International Index of Erectile Function (IIEF-5) and Quality of life (QoL). Not statistically significant differences emerged between the two groups at baseline, both patient groups had similar age and BMI; in each treatment group, the proportion of men ≥ 75 years was approximately 65%. From the results of our study, we can say that a treatment once a day with tadalafil improves not only significantly: micturition/24 hours (p < 0.001), urgency episodes/24 hours (p < 0.003), and urge incontinence episodes (p < 0.001) compared to fesoterodine treatment, but also the quality of life (p < 0.001) and sexual function (p < 0.001) in older patients. These analyses demonstrate that tadalafil 5 mg once daily vs. fesoterodine 8 mg is efficacious in the treatment of the symptoms of OAB in older adults, improving also the quality of life and sexual and social life.

Efficacy and safety of tadalafil in men with erectile dysfunction with a high prevalence of comorbid conditions: results from MOMENTUS: multiple observations in men with erectile dysfunction in National Tadalafil Study in the US.

PubMed

Goldstein, Irwin; Kim, Edward; Steers, William D; Pryor, Jon L; Wilde, Dixon W; Natanegara, Fanni; Wong, David G; Ahuja, Sanjeev

2007-01-01

Limited efficacy and safety data exist from open-label clinical trials of phosphodiesterase 5 inhibitors in men with erectile dysfunction (ED) and multiple comorbid (MCM) conditions, historically a difficult group to treat. A multicenter study (Multiple Observations in Men with Erectile Dysfunction in National Tadalafil Study in the US) assessed efficacy and safety of tadalafil in men with ED and MCM conditions. The primary end point was change from baseline in the erectile function (EF) domain of the International Index of Erectile Function. Secondary end points included the Sexual Encounter Profile, Global Assessment Questions, and Sexual Self-Confidence and Spontaneity Domains of the Psychological and Interpersonal Relationship Scales. This was an open-label, multicenter study in men with ED. Tadalafil 20 mg was administered as needed prior to sexual activity, up to once/day, for 12 weeks following a 4-week ED-treatment-free period. The MCM group was 155 of 1,911 men enrolled in this study. Men in the MCM group met eligibility criteria but could not be included in other predefined groups: (i) Caucasian; (ii) Black American; (iii) Hispanic (groups 1-3, < or =65 years, no diabetes or depression); (iv) depression, < or =65 years, no diabetes; (v) diabetes, < or =65 years, no depression; (vi) >65 years, no diabetes or depression; and (vii) ED subsequent to traumatic spinal cord injury. Mean baseline EF domain score in MCM (mean age 65 +/- 9 years) was 12.2 +/- 6.5; 52% of subjects had severe ED; 72% diabetes mellitus; 67% cardiovascular disease (including hypertension); 49% hyperlipidemia; 38% depression; 84% had two or more comorbidities. At end point, there was a significant (P < 0.001) mean change of 7.6 from baseline in mean EF domain score. Among men with severe ED, 22% achieved an EF domain score > or =26. Most common adverse events were headache 5.2%; flushing 3.9% and nasal congestion 3.2%; 3% discontinued use because of an adverse event. In this open

Sildenafil increases digital skin blood flow during all phases of local cooling in primary Raynaud's phenomenon

PubMed Central

Roustit, Matthieu; Hellmann, Marcin; Cracowski, Claire; Blaise, Sophie; Cracowski, Jean-Luc

2012-01-01

Digital skin vasoconstriction on local cooling is exaggerated in primary Raynaud’s phenomenon (RP) compared to controls. A significant part of such vasoconstriction relies on the nitric oxide (NO) pathway inhibition. We tested the effect of PDE5 inhibitor sildenafil, which potentiates the effect of NO, on skin blood flow. We recruited 15 patients with primary RP, performing local cooling without sildenafil (day 1), after a single 50 mg oral dose (day 2), and 100 mg (day 3). Skin blood flow, skin temperature and arterial pressure were recorded, and data were expressed as cutaneous vascular conductance (CVC). Sildenafil at 100 mg, but not 50 mg, significantly lessened the cooling-induced decrease in CVC. It also increased resting CVC and skin temperature. These data suggest that 100 mg sildenafil improves digital skin blood flow to local cooling in primary RP. The benefit of sildenafil “as required” should be confirmed in a randomized controlled trial. PMID:22453196

Sildenafil Attenuates Hepatocellular Injury after Liver Ischemia Reperfusion in Rats: A Preliminary Study

PubMed Central

Savvanis, Spyridon; Nastos, Constantinos; Tasoulis, Marios-Konstantinos; Papoutsidakis, Nikolaos; Demonakou, Maria; Karmaniolou, Iosifina; Arkadopoulos, Nikolaos; Smyrniotis, Vassilios; Theodoraki, Kassiani

2014-01-01

We evaluated the role of sildenafil in a rat liver ischemia-reperfusion model. Forty male rats were randomly allocated in four groups. The sham group underwent midline laparotomy only. In the sildenafil group, sildenafil was administered intraperitoneally 60 minutes before sham laparotomy. In the ischemia-reperfusion (I/R) group, rats were subjected to 45 minutes of hepatic ischemia followed by 120 minutes of reperfusion, while in the sild+I/R group rats were subjected to a similar pattern of I/R after the administration of sildenafil, 60 minutes before ischemia. Two hours after reperfusion, serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured and histopathological examination of the lobes subjected to ischemia as well as TUNEL staining for apoptotic bodies was performed. Additionally, myeloperoxidase (MPO) activity and the expression of intercellular adhesion molecule-1 (ICAM-1) were analyzed. Serum markers of hepatocellular injury were significantly lower in the sild+I/R group, which also exhibited lower severity of histopathological lesions and fewer apoptotic bodies, as compared to the I/R group. The I/R group showed significantly higher MPO activity and higher expression of ICAM-1, as compared to the sild+I/R group. Use of sildenafil as a preconditioning agent in a rat model of liver I/R exerted a protective effect. PMID:24999378

Sildenafil Promotes eNOS Activation and Inhibits NADPH Oxidase in the Transgenic Sickle Cell Mouse Penis

PubMed Central

Musicki, Biljana; Bivalacqua, Trinity J.; Champion, Hunter C.; Burnett, Arthur L.

2014-01-01

Introduction Sickle cell disease (SCD)-associated vasculopathy in the penis is characterized by aberrant nitric oxide and phosphodiesterase (PDE) 5 signaling, and by increased oxidative stress. Preliminary clinical trials show that continuous treatment with PDE5 inhibitor sildenafil unassociated with sexual activity decreases priapic activity in patients with SCD. However, the mechanism of its vasculoprotective effect in the penis remains unclear. Aims We evaluated whether continuous administration of PDE5 inhibitor sildenafil promotes eNOS function at posttranslational levels and decreases superoxide-producing enzyme NADPH oxidase activity in the sickle cell mouse penis. Methods SCD transgenic mice were used as an animal model of SCD. WT mice served as controls. Mice received treatment with the PDE5 inhibitor sildenafil (100 mg/kg/day) or vehicle for 3 weeks. eNOS phosphorylation on Ser-1177 (positive regulatory site), eNOS interactions with heat-shock protein 90 (HSP90) (positive regulator), phosphorylated AKT (upstream mediator of eNOS phosphorylation on Ser-1177), an NADPH oxidase catalytic subunit gp91(phox), and a marker of oxidative stress (4-hydroxy-2-nonenal [HNE]) were measured by Western blot. Main Outcome Measures Effect of continuous sildenafil treatment on eNOS posttranslational activation, NADPH oxidase catalytic subunit, and oxidative stress in the penis of the sickle cell mouse. Results Continuous treatment with sildenafil reversed (P < 0.05) the abnormalities in protein expressions of P-eNOS (Ser-1177), eNOS/HSP90 interaction, P-AKT, protein expression of gp91(phox), and 4-HNE, in the sickle cell mouse penis. Sildenafil treatment of WT mice did not affect any of these parameters. Conclusion Our findings that sildenafil enhances eNOS activation and inhibits NADPH oxidase function in the sickle cell mouse penis offers a vasculoprotective molecular basis for the therapeutic effect of sildenafil in the penis in association with SCD. PMID:24251665

Sildenafil promotes eNOS activation and inhibits NADPH oxidase in the transgenic sickle cell mouse penis.

PubMed

Musicki, Biljana; Bivalacqua, Trinity J; Champion, Hunter C; Burnett, Arthur L

2014-02-01

Sickle cell disease (SCD)-associated vasculopathy in the penis is characterized by aberrant nitric oxide and phosphodiesterase (PDE) 5 signaling, and by increased oxidative stress. Preliminary clinical trials show that continuous treatment with PDE5 inhibitor sildenafil unassociated with sexual activity decreases priapic activity in patients with SCD. However, the mechanism of its vasculoprotective effect in the penis remains unclear. We evaluated whether continuous administration of PDE5 inhibitor sildenafil promotes eNOS function at posttranslational levels and decreases superoxide-producing enzyme NADPH oxidase activity in the sickle cell mouse penis. SCD transgenic mice were used as an animal model of SCD. WT mice served as controls. Mice received treatment with the PDE5 inhibitor sildenafil (100 mg/kg/day) or vehicle for 3 weeks. eNOS phosphorylation on Ser-1177 (positive regulatory site), eNOS interactions with heat-shock protein 90 (HSP90) (positive regulator), phosphorylated AKT (upstream mediator of eNOS phosphorylation on Ser-1177), an NADPH oxidase catalytic subunit gp91(phox), and a marker of oxidative stress (4-hydroxy-2-nonenal [HNE]) were measured by Western blot. Effect of continuous sildenafil treatment on eNOS posttranslational activation, NADPH oxidase catalytic subunit, and oxidative stress in the penis of the sickle cell mouse. Continuous treatment with sildenafil reversed (P < 0.05) the abnormalities in protein expressions of P-eNOS (Ser-1177), eNOS/HSP90 interaction, P-AKT, protein expression of gp91(phox), and 4-HNE, in the sickle cell mouse penis. Sildenafil treatment of WT mice did not affect any of these parameters. Our findings that sildenafil enhances eNOS activation and inhibits NADPH oxidase function in the sickle cell mouse penis offers a vasculoprotective molecular basis for the therapeutic effect of sildenafil in the penis in association with SCD. © 2013 International Society for Sexual Medicine.

Impact of erectile dysfunction and its subsequent treatment with sildenafil: qualitative study.

PubMed

Tomlinson, John; Wright, David

2004-05-01

To determine the effects of erectile dysfunction and to explore the impact of treatment with sildenafil (Viagra). An exploratory qualitative study with semistructured interviews. Men's health clinic in NHS hospital. 40 men who had had erectile dysfunction and had attended the clinic during the year before interview. Impact of erectile dysfunction on men, their expectations of sildenafil, and impact of treatment on men and their relationships. Issues explored with exploratory qualitative approach. Erectile dysfunction caused serious distress to all those men who experienced it, with marked effects on their self esteem and their relationships. Sildenafil, when it worked, caused a great improvement in wellbeing. The expectations raised by media hyperbole with the launch of sildenafil had an adverse effect on the morale of those who found it did not work. When, according to the patient, treatment did not work, the distress was severe and for many confirmed their lack of self worth. Further study is needed to explore the feelings of men affected by erectile dysfunction and their perception of treatment. Health professionals should be aware of the extreme distress erectile dysfunction can cause.

Protective effect of sildenafil citrate on contralateral testis injury after unilateral testicular torsion/detorsion.

PubMed

Yíldíz, Hamit; Durmus, Ali Said; Simşek, Halil; Yaman, Mine

2011-01-01

This study was designed to investigate prevention of contralateral testicular injury with sildenafil citrate after unilateral testicular torsion/detorsion. Thirty-seven adult male rats were divided into four groups: sham operated (group 1, n = 7), torsion/detorsion + saline (group 2, n = 10), torsion/detorsion + 0.7 mg of sildenafil citrate (group 3, n = 10) and torsion/detorsion + 1.4 mg of sildenafil citrate (group 4, n = 10). Unilateral testicular torsion was created by rotating the right testis 720º in a clockwise direction for 2 h in other groups, except for group 1, which was served as sham group. After torsion (2 h) and detorsion (2 h) periods, rats were killed. The level of reduced glutathion (GSH) (p < 0.05) and the activities of catalase (p < 0.01) and glutathione peroxidase (p < 0.05) in the contralateral testis from group 2 were significantly lower and nitric oxide (NO) (p < 0.05) level in the contralateral testis were significantly higher than those of group 1. Administration of low-dose sildenafil citrate (group 3) prevented the increases in malondialdehyde and NO levels and decreases in glutathione peroxidase activities and GSH values induced by testicular torsion. However, administration of high-dose sildenafil citrate (group 4) had no effect on these testicular parameters (p > 0.05). Histopathological changes were detected in groups 2, 3 and 4. These results suggest that biochemically and histologically torsion/detorsion injury occurs in the contralateral testis following 2-h torsion and 2-h detorsion and that administration of low-dose sildenafil citrate before detorsion prevents ischemia/reperfusion cellular damage in testicular tissue.

Effect of sildenafil on the activity of some antidepressant drugs and electroconvulsive shock treatment in the forced swim test in mice.

PubMed

Socała, Katarzyna; Nieoczym, Dorota; Wyska, Elżbieta; Wlaź, Piotr

2017-04-01

Sildenafil, a potent and selective inhibitor of phosphodiesterase type 5, is used clinically to treat erectile dysfunction and pulmonary arterial hypertension. It is often taken by patients suffering from depression and receiving antidepressant drug treatment. However, its influence on the efficacy of antidepressant treatment was not sufficiently studied. Therefore, the aim of the present study was to investigate the influence of sildenafil on the anti-immobility action of several antidepressant drugs (i.e., sertraline, fluvoxamine, citalopram, maprotiline, trazodone, and agomelatine) as well as on antidepressant-like effect of electroconvulsive stimulations in the forced swim test in mice. The obtained results showed that acute sildenafil treatment enhanced the antidepressant-like activity of all of the studied drugs. The observed effects were not due to the increase in locomotor activity. The interactions between sildenafil and sertraline, maprotiline, and trazodone were pharmacodynamic in nature, as sildenafil did not affect concentrations of these drugs neither in serum nor in brain tissue. Increased concentrations of fluvoxamine, citalopram, and agomelatine in brain tissue evoked by sildenafil co-administration suggest that pharmacokinetic interactions between sildenafil and these drugs are very likely. Sildenafil injected acutely did not alter the antidepressant-like efficacy of electroconvulsive stimulations in mice, as assessed in the forced swim test. Interestingly, repeated (14 days) administration of sildenafil decreased the anti-immobility action of the electroconvulsive stimulations. In conclusion, the present study shows that sildenafil may alter the effectiveness of antidepressant treatment. Further studies are warranted to better characterize the influence of sildenafil on the activity of antidepressant drugs and electroconvulsive therapy.

Long-term effects of sildenafil in a rat model of chronic mitral regurgitation: benefits of ventricular remodeling and exercise capacity.

PubMed

Kim, Kyung-Hee; Kim, Yong-Jin; Ohn, Jung-Hun; Yang, Jimin; Lee, Sang-Eun; Lee, Sae-Won; Kim, Hyung-Kwan; Seo, Jeong-Wook; Sohn, Dae-Won

2012-03-20

We tested the hypothesis that chronic treatment with sildenafil attenuates left ventricular (LV) remodeling and prevents exercise intolerance in chronic mitral regurgitation (MR). MR was created in Sprague-Dawley rats by making a hole on the mitral leaflet. Two weeks after MR creation, MR and LV dilatation were confirmed by echocardiography, and rats were randomly assigned to sildenafil treatment (MR+sildenafil group; 50 mg/kg PO twice a day; n=16) or normal saline only (MR group; n=16) and continued for 4 months. Sixteen sham rats were compared with MR rats. After 4 months, LV size was smaller in the MR+sildenafil compared with the MR group (LV end-systolic dimension, 4.7±0.3 for sham versus 5.9±0.3 for MR+sildenafil versus 7.4±0.5 mm for MR; P<0.05; LV end-diastolic dimension, 8.3±0.4 versus 10.5±0.2 versus 11.7±0.61 mm, respectively; P<0.05). LV ejection fraction was greater in the MR+sildenafil group than in the MR group (70.2±2.2 for sham versus 67.0±4.2 for MR+sildenafil versus 58.9±2.5 for MR; P=0.01). Serial treadmill test revealed that exercise capacity was reduced in the MR but not in the MR+sildenafil group. Transcriptional profiling of cardiac apical tissues revealed that gene sets related to inflammatory response, DNA damage response, cell cycle checkpoint, and cellular signaling pathways were significantly enriched by genes with reciprocal changes. Pathological analysis showed that perivascular fibrosis was more prominent in the MR than in the MR+sildenafil group and that the percentage of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells was 2-fold greater in the MR compared with the MR+sildenafil group. Sildenafil significantly attenuates LV remodeling and prevents exercise intolerance in a rat model of chronic MR. This benefit may be associated with the antiapoptotic, anti-inflammatory effects of sildenafil.

The effects of sildenafil after chronic L-NAME administration in male rat sexual behavior.

PubMed

Ferraz, Marcia M D; Quintella, Suelen L; Parcial, André L N; Ferraz, Marcos R

2016-01-01

Ferraz MMD, Quintella SL, Parcial ALN, Ferraz MR. The effects of sildenafil citrate and L-NAME on male rat sexual behaviour. PHARMACOL BIOCHEM BEHAV. Erectile dysfunction (ED) affects up to 50% of men between 40 and 70years of age. Significant advances in the pharmacological treatment of ED occurred in recent years, most notably the introduction of the first oral selective phosphodiesterase type-5 inhibitor, sildenafil. This study investigated the effectiveness of chronic oral treatment with L-NAME in rats as an experimental model of erectile dysfunction to evaluate new pharmacological agents that affect the sexual response. The effects of chronic oral L-NAME treatment, separately or in combination with sildenafil, on the sexual behaviour of male rats were evaluated. Filtered water was used as a control. Acute administration of L-NAME did not alter the sexual response compared with control, but sildenafil administration facilitated sexual behaviour after acute and chronic administration. Chronic L-NAME treatment inhibited motivational and consummatory measures of male rat sexual behaviour. Sildenafil prevented the inhibitory effects of L-NAME. The present results confirm that chronic oral treatment with a nitric oxide synthase inhibitor may be a relevant peripheral ED model to evaluate the effects of drugs on erectile function of male rats. Copyright © 2016 Elsevier Inc. All rights reserved.

Effect of the selective phosphodiesterase type 5 inhibitor sildenafil on erectile dysfunction in the anesthetized dog.

PubMed

Carter, A J; Ballard, S A; Naylor, A M

1998-07-01

The effects of sildenafil, a highly selective inhibitor of cyclic guanosine monophosphate-specific phosphodiesterase type 5, on erectile function in the anesthetized dog were evaluated. In pentobarbital-anesthetized dogs, increases in intracavernosal pressure in the corpus cavernosum and penile blood flow were induced by pelvic nerve stimulation over a frequency range of 1 to 16 hertz. The effects of increasing doses of sildenafil on electrically stimulated intracavernosal pressure, penile blood flow, blood pressure, and heart-rate were evaluated. In parallel experiments, the effects of the nitric oxide synthase inhibitor N omega-Nitro-L-Arginine (L-NOArg) on these same parameters also were assessed. The effects of nerve stimulation on intracavernosal pressure and blood flow to the penis were blocked by L-NOArg, 0.1-3 mg./kg., in a dose-related manner, confirming the important role of nitric oxide in producing erections. Sildenafil, 1-100 microg./kg administered intravenously, had no direct effect on intracavernosal pressure but potentiated the increase in intracavernosal pressure induced by nerve stimulation. This potentiation occurred at sildenafil plasma concentrations consistent with its relaxation effect on isolated human cavernosal tissue and its inhibition of phosphodiesterase type 5 in vitro. Sildenafil had no significant effect on blood pressure or heart rate. By inhibiting cyclic guanosine monophosphate-specific phosphodiesterase type 5, sildenafil augments the neuronal mechanism responsible for penile erection. This mechanism explains the significant improvements reported in the rigidity and duration of erections seen in patients with erectile dysfunction who have been treated with oral sildenafil.

A comparative study of sildenafil, NCX-911 and BAY41-2272 on the anococcygeus muscle of diabetic rats.

PubMed

Kalsi, Jasjit S; Ralph, David J; Madge, David J; Kell, Phil D; Cellek, Selim

2004-12-01

We compared the effects of a nitric oxide (NO)-releasing sildenafil (NCX-911), NO-independent soluble guanylate cyclase activator (BAY41-2272) and sildenafil on the anococcygeus muscle from streptozotocin-induced 16-weeks diabetic rats. NCX-911, BAY41-2272 and sildenafil reduced the phenylephrine-induced tone in the control group (EC50=1088.8+/-165.0, 151.6+/-9.3 and 827.1+/-167.3 nM, respectively). The potencies of NCX-911 and BAY41-2272 were not altered, but that of sildenafil was significantly reduced in the diabetic group. EC50 values for NCX-911, BAY41-2272 and sildenafil in the diabetic group were 1765.9+/-303.5, 209.7+/-27.3 and 2842.2+/-640.3 nM, respectively (P<0.05 for sildenafil). Nitrergic relaxation responses were significantly decreased in the diabetic group. The remaining nitrergic relaxation responses were potentiated by BAY41-2272 but not by sildenafil or NCX-911. These results confirm that endogenous NO derived from nitrergic nerves is significantly decreased in diabetes, and suggest that NO-releasing PDE5 inhibitors and NO-independent soluble guanylate cyclase activators could be more useful than PDE5 inhibitors in the treatment of ED in long-term diabetes.

A Phase I proof-of-concept and safety trial of sildenafil to treat cerebral vasospasm following subarachnoid hemorrhage.

PubMed

Washington, Chad W; Derdeyn, Colin P; Dhar, Rajat; Arias, Eric J; Chicoine, Michael R; Cross, DeWitte T; Dacey, Ralph G; Han, Byung Hee; Moran, Christopher J; Rich, Keith M; Vellimana, Ananth K; Zipfel, Gregory J

2016-02-01

Studies show that phosphodiesterase-V (PDE-V) inhibition reduces cerebral vasospasm (CVS) and improves outcomes after experimental subarachnoid hemorrhage (SAH). This study was performed to investigate the safety and effect of sildenafil (an FDA-approved PDE-V inhibitor) on angiographic CVS in SAH patients. A2-phase, prospective, nonrandomized, human trial was implemented. Subarachnoid hemorrhage patients underwent angiography on Day 7 to assess for CVS. Those with CVS were given 10 mg of intravenous sildenafil in the first phase of the study and 30 mg in the second phase. In both, angiography was repeated 30 minutes after infusion. Safety was assessed by monitoring neurological examination findings and vital signs and for the development of adverse reactions. For angiographic assessment, in a blinded fashion, pre- and post-sildenafil images were graded as "improvement" or "no improvement" in CVS. Unblinded measurements were made between pre- and post-sildenafil angiograms. Twelve patients received sildenafil; 5 patients received 10 mg and 7 received 30 mg. There were no adverse reactions. There was no adverse effect on heart rate or intracranial pressure. Sildenafil resulted in a transient decline in mean arterial pressure, an average of 17% with a return to baseline in an average of 18 minutes. Eight patients (67%) were found to have a positive angiographic response to sildenafil, 3 (60%) in the low-dose group and 5 (71%) in the high-dose group. The largest degree of vessel dilation was an average of 0.8 mm (range 0-2.1 mm). This corresponded to an average percentage increase in vessel diameter of 62% (range 0%-200%). The results from this Phase I safety and proof-of-concept trial assessing the use of intravenous sildenafil in patients with CVS show that sildenafil is safe and well tolerated in the setting of SAH. Furthermore, the angiographic data suggest that sildenafil has a positive impact on human CVS.

A comparative review of the options for treatment of erectile dysfunction: which treatment for which patient?

PubMed

Hatzimouratidis, Konstantinos; Hatzichristou, Dimitrios G

2005-01-01

The field of erectile dysfunction (ED) has been revolutionised over the last two decades. Several treatment options are available today, most of which are associated with high efficacy rates and favourable safety profiles. A MEDLINE search was undertaken in order to evaluate all currently available data on treatment modalities for ED. Phosphodiesterase type 5 (PDE5) inhibitors (sildenafil, tadalafil, vardenafil) are currently the first-choice of most physicians and patients for the treatment of ED. PDE5 inhibitors have differences in their pharmacological profiles, the most obvious being the long duration of action of tadalafil, but there are no data supporting superiority for any one of them in terms of efficacy or safety. Sublingual apomorphine has limited efficacy compared with the PDE5 inhibitors, and its use is limited to patients with mild ED. Treatment failures with oral drugs may be due to medication, clinician and patient issues. The physician needs to address all of these issues in order to identify true treatment failures. Patients who are truly unresponsive to oral drugs may be offered other treatment options.Intracavernous injections of alprostadil alone, or in combination with other vasoactive agents (papaverine and phentolamine), remain an excellent treatment option, with proven efficacy and safety over time. Topical pharmacotherapy is appealing in nature, but currently available formulations have limited efficacy. Vacuum constriction devices may be offered mainly to elderly patients with occasional intercourse attempts, as younger patients show limited preference because of the unnatural erection that is associated with this treatment modality. Penile prostheses are generally the last treatment option offered, because of invasiveness, cost and non-reversibility; however, they are associated with high satisfaction rates in properly selected patients. All treatment options are associated with particular strengths and weaknesses. A patient

Evaluation of prophylactic and therapeutic effects of sildenafil on acute radiation proctitis in rats.

PubMed

Yavuz, Erkan; Ercan, Gulcin; Karagulle, Onur Olgac; Bayrak, Busra Yaprak; Biricik, Aytac; Ercetin, Candas; Gokcek, Berk; Yigitbas, Hakan; Kusaslan, Ramazan; Celik, Atilla; Gulcicek, Osman Bilgin

2018-04-01

To investigate the prophylactic and therapeutical effects of sildenafil in a model of acute radiation proctitis (ARP). All experimental procedures of this study was examined by histopathological, immunohistochemical and transmission electron microscopic analysis. Our histopathological evaluations indicated significant increases in lesion severity, cryptic apsis, cryptitis, cryptic distortion, reactive atypia and infiltration depth of the control (proctitis) group. While the prophylaxis group and the treatment group had significantly lower scores. High-dose group showed similar results as prophylaxis group. Histopathological findings of the prophylaxis group was more significant than the treatment group. Immunoreactivities of IL-1β, FGF-2, TNF- α and HIF-1α increased in the control group especially in the epithelial and cryptic regions. On the contrary, sildenafil application caused significant decreases of inflammatory markers in all treatment groups, specifically better results in the prophylaxis group. The sildenafil has anti-inflammatory effects on ARP, as well as protective effects against ARP and the protective effect of sildenafil surpasses its therapeutic effect histopathologically.

Curcumin interacts with sildenafil to kill GI tumor cells via endoplasmic reticulum stress and reactive oxygen/ nitrogen species

PubMed Central

Roberts, Jane L.; Poklepovic, Andrew; Booth, Laurence

2017-01-01

The present studies focused on the ability of the phosphodiesterase 5 (PDE5) inhibitor sildenafil to enhance the anti-cancer properties of clinically relevant concentrations of the dietary diarylheptanoid curcumin. In gastrointestinal tumor cells, sildenafil and curcumin interacted in a greater than additive fashion to kill. Inhibition of the extrinsic apoptotic pathway suppressed killing by ∼50%, as did blockade of the intrinsic apoptotic pathway. Sildenafil and curcumin reduced mTORC1 and mTORC2 activity and increased Beclin1 levels and the numbers of autophagosomes and autolysosomes in cells in a PERK-eIF2α-dependent fashion. Knock down of Beclin1 or ATG5 partially suppressed killing. In contrast, stable knock out of ATG16-L1 unexpectedly enhanced killing, an effect not altered by Beclin1/ATG5 knock down. Curcumin and sildenafil exposure reduced the expression of MCL-1, BCL-XL, thioredoxin and superoxide dismutase 2 (SOD2) in an eIF2α-dependent fashion. Curcumin and sildenafil interacted in a greater than additive fashion to increase the levels of reactive oxygen species; knock down of thioredoxin or SOD2 enhanced killing and over-expression of thioredoxin or SOD2 suppressed killing. In vivo, curcumin and sildenafil interacted to suppress the growth of colon cancer tumors. Multiplex analyses of plasma taken after drug exposure at animal nadir indicated that the levels of M-CSF, CXCL-9, PDGF and G-CSF were significantly increased by [curcumin + sildenafil] and that expression of CXCL1 and CCL5 were significantly reduced. Cells isolated from in vivo treated [curcumin + sildenafil] tumors were resistant to in vitro [curcumin + sildenafil] exposure, a phenotype that was blocked by the colon cancer therapeutic regorafenib. PMID:29245915

Computational study of frontier orbitals, moments, chemical reactivity and thermodynamic parameters of sildenafil

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sachdeva, Ritika, E-mail: ritika.sachdeva21@gmail.com; Kaur, Prabhjot; Singh, V. P.

2016-05-06

Analysis of frontier orbitals of sildenafil has been carried using Density Functional Theory. On the basis of HOMO-LUMO energy, values of global chemical reactivity descriptors such as electronegativity, chemical hardness, softness, chemical potential, electrophilicity index have been calculated. Calculated values of dipole moment, polarizability, hyperpolarizability have also been reported for sildenafil along with its thermodynamic parameters.

Prophylactic sildenafil citrate improves select aspects of sexual function in men treated with radiotherapy for prostate cancer.

PubMed

Zelefsky, Michael J; Shasha, Daniel; Branco, Rebekah Dunn; Kollmeier, Marisa; Baser, Raymond E; Pei, Xin; Ennis, Ronald; Stock, Richard; Bar-Chama, Natan; Mulhall, John P

2014-09-01

We studied adjuvant daily sildenafil citrate during and after radiotherapy for prostate cancer for erectile function preservation. We performed a randomized, prospective trial of 279 patients with localized prostate cancer treated with radiotherapy who received sildenafil citrate (50 mg daily) or placebo (2:1 randomization). Medication/placebo was initiated 3 days before treatment and continued daily for 6 months. Before therapy and 3, 6, 9, 12, 18 and 24 months after radiotherapy patients completed the IIEF questionnaire, including the erectile function domain, the I-PSS questionnaire and the RAND SF-36®. All IIEF domains were scored. At 12 months erectile function scores were better for sildenafil citrate than placebo (p = 0.018), 73% of patients on sildenafil citrate vs 50% on placebo had mild/no erectile dysfunction (p = 0.024) and the sildenafil citrate arm had superior overall satisfaction (p = 0.027) and IIEF total scores (p = 0.043). At 24 months erectile function and IIEF scores were no longer significantly better for sildenafil citrate (p = 0.172 and 0.09, respectively) and yet overall satisfaction scores were higher (p = 0.033). Sexual desire scores in patients who received sildenafil citrate were higher at 24 months although they had completed drug therapy 18 months previously (p = 0.049). At 24 months 81.6% of patients on sildenafil citrate and 56.0% of those on placebo achieved functional erection with or without erectile dysfunction medication (p = 0.045). Daily sildenafil citrate during and after radiotherapy for prostate cancer was associated with improved overall sexual function compared with placebo for various sexual function domains. To our knowledge this is the largest randomized, prospective, controlled trial to show the usefulness of a phosphodiesterase-5 inhibitor as a rehabilitation strategy in patients with prostate cancer who received radiation therapy. Copyright © 2014 American Urological Association Education and Research, Inc

Erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) combined responders to tadalafil after 12 weeks of treatment.

PubMed

Roehrborn, Claus G; Egan, Kathryn B; Miner, Martin M; Ni, Xiao; Wong, David G; Rosen, Raymond C

2016-07-01

To analyse the proportion of men taking tadalafil 5 mg once daily who experience a combined improvement in symptoms of both erectile dysfunction (ED) and lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). The data from men aged ≥45 years randomized to tadalafil 5 mg once daily or placebo enrolled in one of four randomized, placebo-controlled LUTS/BPH clinical trials were analysed (N = 927). A novel classification of 'combined responders' to ED and LUTS/BPH treatment was defined, based on published criteria for men who showed improvement in both International Index of Erectile Function - Erectile Function domain (IIEF-EF) score and total International Prostate Symptom Score (IPSS). Descriptive analyses assessed the covariate distribution by responder status. Unadjusted and adjusted logistic regressions provided odds ratios with 95% confidence intervals comparing combined responders with all others (partial and non-responders). Among men randomized to tadalafil 5 mg, 40.5% were combined responders (n = 189). Among placebo randomized men, 18.3% were combined responders (n = 84). Combined responders, in the total population, had the highest baseline IPSS and lowest baseline IIEF-EF scores, corresponding to the highest level of dysfunction. The majority of men were aged ≤65 years, white, non-obese, non-smokers, and regular alcohol consumers. Only treatment, baseline IPSS, baseline IIEF-EF, obesity and psychoactive medication use were significantly associated with responder status (P ≤ 0.05). Tadalafil-treated men had 2.8 times significantly increased adjusted odds of being combined responders vs non-responders (P < 0.001). For each unit decrease in baseline IIEF-EF or alcoholic drink consumption per week there was a 4% significant increase in the adjusted odds of being a combined responder to tadalafil therapy. This novel measure of combined response is useful in differentiating patients with clinically relevant symptom

Use of intraurethral alprostadil in patients not responding to sildenafil citrate.

PubMed

Jaffe, Jamison S; Antell, Mara R; Greenstein, Marc; Ginsberg, Phillip C; Mydlo, Jack H; Harkaway, Richard C

2004-05-01

To determine whether intraurethral alprostadil would be an effective alternative for men with erectile dysfunction who did not respond adequately to sildenafil citrate but desired minimally invasive treatment. A total of 44 male patients aged 41 to 74 years with erectile dysfunction refractory to treatment with sildenafil citrate were enrolled in this study. Of the 44 patients, 10 had undergone prior radical retropubic prostatectomy. The patients were evaluated for subjective improvement in an office setting and completed the Sexual Health Inventory for Men questionnaire as an objective assessment of improved erectile ability. Success was defined as subjective improvement in erectile function, as well as an improved Sexual Health Inventory for Men score. Of the 44 men, 13 (29.5%) responded successfully to intraurethral alprostadil, with a follow-up ranging from 2 to 15 months. The remaining 31 men had no response (n = 28, 90%), refused escalating doses (n = 2, 7%), or were lost to follow-up (n = 1, 3%). In the subgroup of 10 men with prior radical retropubic prostatectomy, 5 (50%) reported success with intraurethral alprostadil (500 microg in 2 patients and 1000 microg in 3 patients). Although sildenafil citrate remains the most common initial therapy in men with erectile dysfunction, intraurethral alprostadil may be a reasonable treatment option for sildenafil nonresponders. This may be especially true in men having undergone prior radical retropubic prostatectomy.

Sildenafil citrate (Viagra) impairs fertilization and early embryo development in mice.

PubMed

Glenn, David R J; McClure, Neil; Cosby, S Louise; Stevenson, Michael; Lewis, Sheena E M

2009-03-01

To determine the effects of sildenafil citrate, a cyclic monophosphate-specific type 5 phosphodiesterase inhibitor known to affect sperm function, on fertilization and early embryo cleavage. This acute mammal study included male and female mice assigned randomly, the females sacrificed after mating and their oocytes/embryos evaluated at four time periods after treatment. Academic research environment. Male and female CBAB(6) mice. Female mice were injected intraperitoneally with 5 IU gonadotropin (hCG) to stimulate follicular growth and induce ovulation. They were each caged with a male that had been gavaged with sildenafil citrate (0.06 mg/0.05 mL) and allowed to mate. After 12, 36, 60, and 84 h, females were killed, their oviducts were dissected out, and retrieved embryos were assessed for blastomere number and quality. Fertilization rates and numbers of embryos were evaluated after treatment. Fertilization rates (day 1) were markedly reduced (-33%) in matings where the male had taken sildenafil citrate. Over days 2-4, the numbers of embryos developing in the treated group were significantly fewer than in the control group. There was also a trend for impaired cleavage rates within those embryos, although this did not reach significance. The impairments to fertility caused by sildenafil citrate have important implications for infertility centers and for couples who are using this drug precoitally while attempting to conceive.

Tadalafil Reduces Myeloid-Derived Suppressor Cells and Regulatory T Cells and Promotes Tumor Immunity in Patients with Head and Neck Squamous Cell Carcinoma

PubMed Central

Vella, Jennifer L.; Reis, Isildinha M.; De la fuente, Adriana C.; Gomez, Carmen; Sargi, Zoukaa; Nazarian, Ronen; Califano, Joseph; Borrello, Ivan

2015-01-01

Purpose Myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) play a key role in the progression of head and neck squamous cell carcinoma (HNSCC). On the basis of our preclinical data demonstrating that phosphodiesterase-5 (PDE5) inhibition can modulate these cell populations, we evaluated whether the PDE5 inhibitor tadalafil can revert tumor-induced immunosuppression and promote tumor immunity in patients with HNSCC. Experimental Design First, we functionally and phenotypically characterized MDSCs in HNSCCs and determined, retrospectively, whether their presence at the tumor site correlates with recurrence. Then, we performed a prospective single-center, double-blinded, randomized, three-arm study in which patients with HNSCC undergoing definitive surgical resection of oral and oropharyngeal tumors were treated with tadalafil 10 μg/day, 20 μg/day, or placebo for at least 20 days preoperatively. Blood and tumor MDSC and Treg presence and CD8+ T-cell reactivity to tumor antigens were evaluated before and after treatment. Results MDSCs were characterized in HNSCC and their intratumoral presence significantly correlates with recurrence. Tadalafil treatment was well tolerated and significantly reduced both MDSCs and Treg concentrations in the blood and in the tumor (P < 0.05). In addition, the concentration of blood CD8+ T cells reactive to autologous tumor antigens significantly increased after treatment (P < 0.05). Tadalafil immunomodulatory activity was maximized at an intermediate dose but not at higher doses. Mechanistic analysis suggests a possible off-target effect on PDE11 at high dosages that, by increasing intracellular cAMP, may negatively affect antitumor immunity. Conclusions Tadalafil seems to beneficially modulate the tumor micro- and macro-environment in patients with HNSCC by lowering MDSCs and Tregs and increasing tumor-specific CD8+ T cells in a dose-dependent fashion. PMID:25320361

Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial

PubMed Central

Coghlan, John Gerry; Galiè, Nazzareno; Barberà, Joan Albert; Frost, Adaani E; Ghofrani, Hossein-Ardeschir; Hoeper, Marius M; Kuwana, Masataka; McLaughlin, Vallerie V; Peacock, Andrew J; Simonneau, Gérald; Vachiéry, Jean-Luc; Blair, Christiana; Gillies, Hunter; Miller, Karen L; Harris, Julia H N; Langley, Jonathan; Rubin, Lewis J

2017-01-01

Background Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding the benefit of PAH-targeted therapy in some forms of CTD-PAH. Objective To explore the safety and efficacy of initial combination therapy with ambrisentan and tadalafil versus ambrisentan or tadalafil monotherapy in patients with CTD-PAH and SSc-PAH enrolled in the AMBITION trial. Methods This was a post hoc analysis of patients with CTD-PAH and SSc-PAH from AMBITION, an event-driven, double-blind trial in patients with WHO functional class II/III PAH. Treatment-naive patients were randomised 2:1:1 to once-daily initial combination therapy with ambrisentan plus tadalafil or monotherapy with ambrisentan or tadalafil, respectively. The primary endpoint was time to the first clinical failure event (first occurrence of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response). Results In the primary analysis set (N=500), 187 patients had CTD-PAH, of whom 118 had SSc-PAH. Initial combination therapy reduced the risk of clinical failure versus pooled monotherapy in each subgroup: CTD-PAH (HR 0.43 (95% CI 0.24 to 0.77)) and SSc-PAH (0.44 (0.22 to 0.89)). The most common AE was peripheral oedema, which was reported more frequently with initial combination therapy than monotherapy in the two PAH subgroups. The relative frequency of adverse events between those on combination therapy versus monotherapy was similar across subgroups. Conclusions This post hoc subgroup analysis provides evidence that CTD-PAH and SSc-PAH patients benefit from initial ambrisentan and tadalafil combination therapy. Trial registration number NCT01178073, post results. PMID:28039187

Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial.

PubMed

Coghlan, John Gerry; Galiè, Nazzareno; Barberà, Joan Albert; Frost, Adaani E; Ghofrani, Hossein-Ardeschir; Hoeper, Marius M; Kuwana, Masataka; McLaughlin, Vallerie V; Peacock, Andrew J; Simonneau, Gérald; Vachiéry, Jean-Luc; Blair, Christiana; Gillies, Hunter; Miller, Karen L; Harris, Julia H N; Langley, Jonathan; Rubin, Lewis J

2017-07-01

Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding the benefit of PAH-targeted therapy in some forms of CTD-PAH. To explore the safety and efficacy of initial combination therapy with ambrisentan and tadalafil versus ambrisentan or tadalafil monotherapy in patients with CTD-PAH and SSc-PAH enrolled in the AMBITION trial. This was a post hoc analysis of patients with CTD-PAH and SSc-PAH from AMBITION, an event-driven, double-blind trial in patients with WHO functional class II/III PAH. Treatment-naive patients were randomised 2:1:1 to once-daily initial combination therapy with ambrisentan plus tadalafil or monotherapy with ambrisentan or tadalafil, respectively. The primary endpoint was time to the first clinical failure event (first occurrence of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response). In the primary analysis set (N=500), 187 patients had CTD-PAH, of whom 118 had SSc-PAH. Initial combination therapy reduced the risk of clinical failure versus pooled monotherapy in each subgroup: CTD-PAH (HR 0.43 (95% CI 0.24 to 0.77)) and SSc-PAH (0.44 (0.22 to 0.89)). The most common AE was peripheral oedema, which was reported more frequently with initial combination therapy than monotherapy in the two PAH subgroups. The relative frequency of adverse events between those on combination therapy versus monotherapy was similar across subgroups. This post hoc subgroup analysis provides evidence that CTD-PAH and SSc-PAH patients benefit from initial ambrisentan and tadalafil combination therapy. NCT01178073, post results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Inhaled sildenafil nanocomposites: lung accumulation and pulmonary pharmacokinetics.

PubMed

Ghasemian, Elham; Vatanara, Alireza; Rouini, Mohammad Reza; Rouholamini Najafabadi, Abdolhossein; Gilani, Kambiz; Lavasani, Hoda; Mohajel, Nasir

2016-12-01

Administration of sildenafil citrate (SC) is considered as a strategy in the treatment of pulmonary hypertension. This study reports production of the inhalable microparticles containing SC-loaded poly(lactide-co-glycolic acid)-nanoparticles. SC-nanoparticles were prepared by the double emulsion solvent evaporation method. Next, free SC and SC-loaded nanoparticles were spray dried in the presence of appropriate excipients (lactose, maltose and trehalose). Physicochemical properties and aerodynamic behavior of prepared powders were evaluated. In addition, drug accumulation from selected formulations in the rat lung tissue was compared with oral and IV administration. Size and fine particle fraction of selected nanocomposites and free SC microparticles were 7 and 4.5 µm, and 60.2% and 68.2%, respectively. Following oral and IV administration, the drug was not detectable in the lung after 4 and 6 h, respectively, but in SC-loaded nanoparticles, the drug was detectable in the lung even after 12 h of inhalation. Respirable particles containing free SC provided high concentration at first that was detectable up to 6 after insufflation. In vivo study demonstrated that pulmonary administration of sildenafil and sildenafil nanoparticles produced longer half-life and higher concentration of the drug in the lung tissue as compared to oral and IV administration. So, these formulations could be more effective than oral and IV administration of this drug.

Changes in Retinal and Choroidal Vascular Blood Flow after Oral Sildenafil: An Optical Coherence Tomography Angiography Study.

PubMed

Berrones, David; Salcedo-Villanueva, Guillermo; Morales-Cantón, Virgilio; Velez-Montoya, Raul

2017-01-01

To describe changes in the retina and choroidal flow by optical coherence tomography angiography (OCT-A) after a single dose of oral sildenafil. A case-control study. Patients in the study group received 50 mg of oral sildenafil. Patients in the control group received a sham pill. Retinal and choroidal images were obtained at baseline (before pill ingestion) and 1 hour after ingestion. Central macular and choroidal thickness, choroidal and outer retina flow, and the retinal and choroidal vascular density were compared using a Mann-Whitney U test. Twenty eyes were enrolled into the study group and 10 eyes in the control group. There was a significant difference in central choroidal thickness and outer retina blood flow between groups after 1 hour of sildenafil ingestion ( p < 0.01). There were no differences in central macular thickness, choroidal flow, and retinal vascular density among groups. A single dose of oral sildenafil increases choroidal thickness, probably due to sildenafil-induced vasodilation.

Changes in Retinal and Choroidal Vascular Blood Flow after Oral Sildenafil: An Optical Coherence Tomography Angiography Study

PubMed Central

Berrones, David; Morales-Cantón, Virgilio

2017-01-01

Purpose To describe changes in the retina and choroidal flow by optical coherence tomography angiography (OCT-A) after a single dose of oral sildenafil. Method A case-control study. Patients in the study group received 50 mg of oral sildenafil. Patients in the control group received a sham pill. Retinal and choroidal images were obtained at baseline (before pill ingestion) and 1 hour after ingestion. Central macular and choroidal thickness, choroidal and outer retina flow, and the retinal and choroidal vascular density were compared using a Mann-Whitney U test. Results Twenty eyes were enrolled into the study group and 10 eyes in the control group. There was a significant difference in central choroidal thickness and outer retina blood flow between groups after 1 hour of sildenafil ingestion (p < 0.01). There were no differences in central macular thickness, choroidal flow, and retinal vascular density among groups. Conclusions A single dose of oral sildenafil increases choroidal thickness, probably due to sildenafil-induced vasodilation. PMID:29129998

Sildenafil citrate for the management of fetal growth restriction and oligohydramnios

PubMed Central

Choudhary, Rana; Desai, Kavita; Parekh, Hetal; Ganla, Kedar

2016-01-01

Fetal growth restriction (FGR) and preeclampsia are the major causes of neonatal morbidity and mortality, which affect up to 8% of all pregnancies. The pathogenesis in FGR is an abnormal trophoblastic invasion leading to compromised uteroplacental circulation. However, in spite of this understanding and identification of high-risk patients, the management options are limited. There are some new studies which have demonstrated the role of sildenafil citrate in improving vasodilatation of small myometrial vessels and therefore improvement in amniotic fluid index, fetal weight, and even uterine and umbilical artery Doppler patterns. We report here the case of a 31-year-old female with infertility and preconceptional thin endometrium responding well to sildenafil citrate, followed by conception. However, she presented with an early-onset FGR at 26 weeks of gestation, and again after treatment with sildenafil citrate, showed improvement in amniotic fluid index and fetal weight, finally resulting in delivery of a full-term healthy baby with uneventful neonatal course. PMID:27563258

Effects of Sildenafil on Cerebrovascular Reactivity in Patients with Becker Muscular Dystrophy.

PubMed

Lindberg, Ulrich; Witting, Nanna; Jørgensen, Stine Lundgaard; Vissing, John; Rostrup, Egill; Larsson, Henrik Bo Wiberg; Kruuse, Christina

2017-01-01

Patients suffering from Becker muscular dystrophy (BMD) have dysfunctional dystrophin proteins and are deficient in neuronal nitric oxide synthase (nNOS) in muscles. This causes functional ischemia and contributes to muscle wasting. Similar functional ischemia may be present in brains of patients with BMD, who often have mild cognitive impairment, and nNOS may be important for the regulation of the microvascular circulation in the brain. We hypothesized that treatment with sildenafil, a phosphodiesterase type 5 inhibitor that potentiates nitric oxide responses, would augment both the blood oxygen level-dependent (BOLD) response and cerebral blood flow (CBF) in patients with BMD. Seventeen patients (mean ± SD age 38.5 ± 10.8 years) with BMD were included in this randomized, double-blind, placebo-controlled, crossover trial. Twelve patients completed the entire study. Effects of sildenafil were assessed by 3 T magnetic resonance (MR) scanning, evoked potentials, somatosensory task-induced BOLD functional MR imaging, regional and global perfusion, and angiography before and after 4 weeks of sildenafil, 20 mg (Revatio in gelatine capsules, oral, 3 times daily), or placebo treatment. Sildenafil increased the event-related sensory and visual BOLD response compared with placebo (p < 0.01). However, sildenafil did not alter CBF, measured by MR phase contrast mapping, or the arterial diameter of the middle cerebral artery, measured by MR angiography. We conclude that nNOS may play a role in event-related neurovascular responses. Further studies in patients with BMD may help clarify the roles of dystrophin and nNOS in neurovascular coupling in general, and in patients with BMD in particular.

A randomized, open-label 3-way crossover study to investigate the relative bioavailability and bioequivalence of crushed sildenafil 20 mg tablets mixed with apple sauce, extemporaneously prepared suspension (EP), and intact sildenafil 20 mg tablets in healthy volunteers under fasting conditions.

PubMed

Gao, Xiang; Ndongo, Marie-Noella; Checchio, Tina M; Cook, Jack; Duncan, Barbara; LaBadie, Robert R

2015-01-01

The relative bioavailability and bioequivalence of 20-mg doses of a pediatric formulation of sildenafil extemporaneous preparation suspension (EP; 10 mg/mL), the sildenafil 20-mg intact tablet and the crushed sildenafil 20-mg tablet mixed with apple sauce were assessed in a single-dose, randomized, open-label, 3-way crossover study with 18 healthy adult volunteers. Blood samples were collected at predefined times and analyzed for sildenafil plasma concentrations. Natural log-transformed sildenafil pharmacokinetic parameters (Cmax , AUClast , and AUCinf ) were used to estimate relative bioavailability and construct 90% confidence intervals (CI) using a mixed-effects model. Bioequivalence was concluded among the three formulations with one exception, in which the EP suspension showed a 15% decrease in Cmax with a lower 90% CI of 76% compared with the intact tablet. The 15% decrease in sildenafil Cmax is not considered to be clinically relevant. Therefore, the EP suspension is considered to be an appropriate pediatric formulation. All 3 formulations were well tolerated in healthy adult volunteers. © 2014, The American College of Clinical Pharmacology.

Chronic treatment with tadalafil improves endothelial function in men with increased cardiovascular risk.

PubMed

Rosano, Giuseppe M C; Aversa, Antonio; Vitale, Cristiana; Fabbri, Andrea; Fini, Massimo; Spera, Giovanni

2005-02-01

Erectile dysfunction (ED) is often associated with a cluster of risk factors for coronary artery disease and reduced endothelial function. Acute and chronic administration of oral sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, improves endothelial function in patients with ED. Tadalafil (TAD) is a new PDE5 inhibitor with a long half life that allows alternate day administration. Aim of the study was to evaluate whether chronic therapy (4 weeks) with TAD improves endothelial function in patients with increased cardiovascular risk and whether this effect is sustained after discontinuation of therapy. We randomized 32 patients with increased cardiovascular risk to receive either TAD 20 mg on alternate days or matching placebo (PLB) for 4 weeks. Patients underwent evaluation of brachial artery flow-mediated dilation (FMD), nitrite/nitrate and endothelin-1 plasma levels at baseline, at the end of treatment period and after two-weeks follow-up. At 4 weeks, FMD was significantly improved by TAD (from 4.2+/-3.2 to 9.3+/-3.7%, p<0.01 vs. baseline), but was not modified by PLB (from 4.1+/-2.8 to 4.0+/-3.4%, p=NS). At 6 weeks the benefit in FMD was sustained in patients that received TAD (9.1+/-3.9% vs. 4.2+/-3.2%, p=0.01 vs. baseline; 9.1+/-3.9% vs. 9.3+/-3.7%, vs. 4 weeks, p=NS) while no changes in FMD were observed in patients randomized to PLB. Also, compared to baseline, a net increase in nitrite/nitrate levels (38.2+/-12.3 vs. 52.6+/-11.7 and 51.1+/-3.1, p<0.05) and a decrease in endothelin-1 levels (3.3+/-0.9 vs. 2.9.+/-0.7 and 2.9+/-0.9, p<0.05) was found both at four and six-weeks after TAD; these changes were inversely correlated as shown by regression analysis (adjusted R2=0.81, p<0.0001). Chronic therapy with TAD improves endothelial function in patients with increased cardiovascular risk regardless their degree of ED. The benefit of this therapy is sustained for at least two weeks after the discontinuation of therapy. Larger studies are needed in order

Optimized sildenafil citrate fast orodissolvable film: a promising formula for overcoming the barriers hindering erectile dysfunction treatment.

PubMed

Hosny, Khaled Mohamed; El-Say, Khalid Mohamed; Ahmed, Osama Abdelhakim

2016-01-01

Sildenafil citrate, a drug used to treat erectile dysfunction, is available in tablet form but has three major problems. First, the drug displays poor aqueous solubility, which delays its onset of action. Second, the drug undergoes extensive first-pass metabolism, resulting in a low (40%) bioavailability. Third, the gastrointestinal effects of sildenafil citrate include dyspepsia and a burning sensation. The objective of this study was to prepare sildenafil citrate using a fast orodissolvable film (ODF) containing the drug in a solid dispersion (SD) to mitigate the abovementioned problems. The solubility of sildenafil citrate in β-cyclodextrin derivatives was estimated, and SDs were prepared and characterized. To develop an ODF that disintegrates rapidly and releases the maximum amount of sildenafil citrate, a 3(3) Box-Behnken experimental design was used to estimate the effects of different concentrations of film forming polymer (X1), the film modifier (X2), and the plasticizer (X3) on the responses, i.e. the disintegration time (Y1) and the amount of drug released (Y2). Pharmacokinetic studies with the optimized (ODF) were conducted on human volunteers. SD prepared using hydroxybutyl-β-cyclodextrin enhanced the solubility of sildenafil citrate by more than eightfold. The Y1 for the optimized ODF was 89 seconds, and the Y2 was 86%; this formula also exhibited a rapid onset of action, and its bioavailability was enhanced by 2.25-fold compared with that of the marketed tablet. The ODF is a promising formulation for sildenafil citrate that results in higher solubility, a rapid onset of action, and enhanced systemic bioavailability.

Improved pulmonary function in the nitrofen model of congenital diaphragmatic hernia following prenatal maternal dexamethasone and/or sildenafil.

PubMed

Burgos, Carmen Mesas; Pearson, Erik G; Davey, Marcus; Riley, John; Jia, Huimin; Laje, Pablo; Flake, Alan W; Peranteau, William H

2016-10-01

Pulmonary hypoplasia and hypertension is a leading cause of morbidity and mortality in congenital diaphragmatic hernia (CDH). The etiologic insult occurs early in gestation highlighting the potential of prenatal interventions. We evaluated prenatal pharmacologic therapies in the nitrofen CDH model. Olive oil or nitrofen were administered alone or with dexamethasone (DM), sildenafil, or DM+sildenafil to pregnant rats. Newborn pups were assessed for lung function, structure and pulmonary artery (PA) flow and resistance. Prenatal DM treatment of CDH pups increased alveolar volume density (Vva), decreased interalveloar septal thickness, increased tidal volumes and improved ventilation without improving oxygenation or PA resistance. Sildenafil decreased PA resistance and improved oxygenation without improving ventilation or resulting in significant histologic changes. DM+sildenafil decreased PA resistance, improved oxygenation and ventilation while increasing Vva and decreasing interalveolar septal and pulmonary arteriole medial wall thickness. Lung and body weights were decreased in pups treated with DM and/or sildenafil. Prenatal DM or sildenafil treatment increased pulmonary compliance and decreased pulmonary vascular resistance respectively, and was associated with improved neonatal gas exchange but had a detrimental effect on lung and fetal growth. This study highlights the potential of individual and combined prenatal pharmacologic therapies for CDH management.

Sildenafil citrate improves erectile function after castration in a rat model.

PubMed

Mulhall, John P; Verma, Nipun; Deveci, Serkan; Tal, Raanan; Kobylarz, Keith; Müller, Alexander

2014-04-01

The administration of phosphodiesterase 5 inhibitor commencing at the time of castration might preserve erectile function. To determine if sildenafil citrate treatment could improve erectile function after castration. To determine if sildenafil citrate treatment reduces collagenisation and apoptosis in erectile tissue after castration. In all, 60 Sprague-Dawley rats were studied; the rats were divided into the following groups: sham - no orchidectomy (S), control - orchidectomy only (O) and treatment - orchidectomy plus sildenafil treatment (V), with 10 rats per group. Erectile haemodynamics assessment was done at 7 days (S7, O7, V7) and at 28 days (S28, O28, V28) yielding a total of six groupings. Functional assessment measured the mean maximum intracavernosal pressure-mean arterial pressure (ICP/MAP) ratio. TUNEL assay was used to define apoptotic indices (AIs) and Masson's trichrome staining was used to evaluate smooth muscle-collagen (SM-C) ratios. The S28 group had the highest and the O7 group the lowest ICP/MAP ratio, at a mean (sd) of 70 (6)% and 36 (6)%, respectively. Both treatment groups, V7 [42 (12)%] and V28 [49 (13)%] showed statistically significant improvements over their corresponding control groups: O7 [36 (6)%] and O28 [37 (9)%] (P < 0.05). However, ICP/MAP values for V7 and V28 remained significantly below the S28 group (P < 0.001). There were no significant differences in ICP/MAP values between the 28-day and 7-day ICP/MAP ratios within each group (S, O, V). There were no significant differences in SM-C ratio between the O and V groups (O7 vs V7, P = 0.45; O28 vs V28, P = 0.16). There were no significant differences in AIs between the O and V groups (O7 vs V7, P = 0.54; O28 vs V28, P = 0.8). Daily treatment with sildenafil improved erectile function in rats after castration. ICP/MAP ratios increased significantly in the treatment groups compared with the control groups with the greatest erectile function occurring 28 days from administration. In

Effect of sildenafil citrate on secondary healing in full thickness skin defects in experiment.

PubMed

Cakmak, E; Karasoy Yesilada, A; Sevim, K Z; Sumer, O; Tatlidede, H S; Sakiz, D

2014-01-01

An acceleration of the wound healing process expedites chronic wound patient's return to normal social environments significantly. Sildenafil, a cyclic guanosine monophosphate (cGMP)-dependent phosphodiesterase- 5 inhibitor has been shown to be a potent stimulator of angiogenesis through upregulation of cGMP. In our study, sildenafil was administered orally as a cost-effective supplement in the treatment of full thickness defects and chronic wounds in that manner with low incidence of side effects and morbidity. Randomly selected 72 Wistar-Albino rats were divided into the two groups, 36 rats in each group. Control group (n =36) was divided further into a secondary healing group consisting of 9 rats and a pathology group consisting of 27 rats (pathology group 1: 9 rats, 4th and 7th day of wound healing, pathology group 2: 9 rats, 10th and 14th day of wound healing, pathology group 3: 9 rats, 21st and 28th day of wound healing. Experimental group consisted of 36 rats which received sildenafil citrate (Viagra® Pfizer, Germany) for secondary wound healing to proceed. The average wound healing period in the control group was 17.89 days and in the sildenafil citrate administered group 14.56 days. The difference of the epithelialisation on full thickness defects were more prominent on days 5 and 11 postoperatively. In the sildenafil citrate applied group, on the 7th day, the defect was 25% smaller and on the 13th day, the defect contracted by 38%. In conclusion, we believe that sildenafil citrate administered orally is a cost- effective supplement in the treatment of full thickness defects and chronic wounds in that manner with low incidence of side effects and morbidity (Tab. 4, Fig. 7, Ref. 34).

Perinatal and Hemodynamic Evaluation of Sildenafil Citrate for Preeclampsia Treatment: A Randomized Controlled Trial.

PubMed

Trapani, Alberto; Gonçalves, Luis Flavio; Trapani, Thamyris Finger; Vieira, Simone; Pires, Marilen; Pires, Maria Marlene de Souza

2016-08-01

To evaluate whether therapy with sildenafil citrate prolongs gestation in women with preeclampsia. In a randomized double-blind, placebo-controlled trial, 100 singleton pregnancies with preeclampsia between 24 and 33 weeks of gestation were randomized to 50 mg oral sildenafil citrate every 8 hours or placebo. The primary outcome was prolongation of pregnancy from randomization to delivery. Secondary outcomes were changes in resistance indices of uterine, umbilical, and middle cerebral arteries by Doppler, fetal and maternal complications, and adverse neonatal outcomes. Power analysis estimated that to detect a difference of 5 days in pregnancy duration, 43 patients would have to be randomized to each group. From June 2013 to October 2015, 50 patients were randomized to each group. Pregnancy duration was on average 4 days longer (14.4 days, 95% confidence interval [CI] 12.5-16.6 days compared with 10.4 days, 95% CI 8.4-12.3 days, P=.008) and percent reduction in pulsatility indices of uterine and umbilical arteries higher (22.5% and 18.5%, compared with placebo 2.1% and 2.5%, P<.001) for patients treated with sildenafil compared with placebo. Maternal blood pressure before and 24 hours after randomization was lower with sildenafil (sildenafil: 100.3±5.6 mm Hg compared with 116.4±5.1 mm Hg, P<.05; placebo: 110.6±6.2 mm Hg compared with 114.7±6.5 mm Hg, P=.21). There was no difference in perinatal morbidity, mortality, or adverse effects between groups. Therapy with sildenafil citrate was associated with pregnancy prolongation of approximately 4 days compared with placebo in women with preeclampsia. Brazilian Registry of Clinical Trials, www.ensaiosclinicos.gov.br, RBR-8qj4p5.

Sildenafil improves heart rate variability in dogs with asymptomatic myxomatous mitral valve degeneration

PubMed Central

PIRINTR, Prapawadee; SAENGKLUB, Nakkawee; LIMPRASUTR, Vudhiporn; SAWANGKOON, Suwanakiet; KIJTAWORNRAT, Anusak

2017-01-01

Myxomatous mitral valve degeneration (MMVD) causes an imbalance of sympathovagal activity resulted in poor cardiac outcomes. Phosphodiesterase-5 inhibitors have been revealed cardioprotective effect in patients with heart diseases. This study aimed to 1) compare the heart rate variability (HRV) between asymptomatic MMVD and healthy dogs and 2) assess long-term effects of sildenafil and enalapril on time- and frequency-domains analyzes. Thirty-four dogs with MMVD stage B1 or B2 and thirteen healthy dogs were recruited into the study. MMVD dogs were divided into 3 subgroups: control (n=13), sildenafil (n=12) and enalapril (n=9). HRV was analyzed from 1-hr Holter recording at baseline (D0) in all dogs and at 30, 90 and 180 days after treatment. The results showed that MMVD dogs had significant higher heart rate (HR), systemic blood pressures, the ratio of low to high frequency (LF/HF) and had significant decreased standard deviation of all normal to normal RR intervals (SDNN) and the percentage of the number of normal-to-normal sinus RR intervals with differences >50 msec computed over the entire recording (pNN50) when compared with healthy dogs (P<0.05). Neither time nor frequency domain parameters were different among subgroups of MMVD dogs at D0. After treatment with sildenafil for 90 days, both time- and frequency-domain parameters were significantly increased when compared with control and enalapril groups. This study demonstrated that sildenafil improves HRV in asymptomatic MMVD dogs suggesting that sildenafil should be used in the MMVD dogs to restore the sympathovagal balance. PMID:28717064

Phosphodiesterase-5 inhibitor sildenafil preconditions adult cardiac myocytes against necrosis and apoptosis. Essential role of nitric oxide signaling.

PubMed

Das, Anindita; Xi, Lei; Kukreja, Rakesh C

2005-04-01

We investigated the effect of sildenafil in protection against necrosis or apoptosis in cardiomyocytes. Adult mouse ventricular myocytes were treated with sildenafil (1 or 10 microM) for 1 h before 40 min of simulated ischemia (SI). Necrosis was determined by trypan blue exclusion and lactate dehydrogenase release following SI alone or plus 1 or 18 h of reoxygenation (RO). Apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated nick end labeling assay and mitochondrial membrane potential measured using a fluorescent probe 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolyl-carbocyanine iodide (JC-1). Sildenafil reduced necrosis as indicated by decrease in trypan blue-positive myocytes and leakage of lactate dehydrogenase compared with untreated cells after either SI or SI-RO. The number of terminal deoxynucleotidyl transferase-mediated nick end labeling-positive myocytes or loss of JC-1 fluorescence following SI and 18 h of RO was attenuated in the sildenafil-treated group with concomitant inhibition of caspase 3 activity. An early increase in Bcl-2 to Bax ratio with sildenafil treatment was also observed in myocytes after SI-RO. The increase of Bcl-2 expression by sildenafil was inhibited by nitric-oxide synthase (NOS) inhibitor, L-nitro-amino-methyl-ester. The drug also enhanced mRNA and protein content of inducible NOS (iNOS) and endothelial NOS (eNOS) in the myocytes. Sildenafil-induced protection against necrosis and apoptosis was absent in the myocytes derived from iNOS knock-out mice and was attenuated in eNOS knock-out myocytes. The up-regulation of Bcl-2 expression by sildenafil was also absent in iNOS-deficient myocytes. Reverse transcription-PCR, Western blots, and immunohistochemical assay confirmed the expression of phosphodiesterase-5 in mouse cardiomyocytes. These data provide strong evidence for a direct protective effect of sildenafil against necrosis and apoptosis through NO signaling pathway. The results may have possible

Efficacy of sildenafil on ischaemic digital ulcer healing in systemic sclerosis: the placebo-controlled SEDUCE study

PubMed Central

Hachulla, Eric; Hatron, Pierre-Yves; Carpentier, Patrick; Agard, Christian; Chatelus, Emmanuel; Jego, Patrick; Mouthon, Luc; Queyrel, Viviane; Fauchais, Anne-Laure; Michon-Pasturel, Ulrique; Jaussaud, Roland; Mathian, Alexis; Granel, Brigitte; Diot, Elisabeth; Farge-Bancel, Dominique; Mekinian, Arsène; Avouac, Jérôme; Desmurs-Clavel, Hélène; Clerson, Pierre

2016-01-01

Objective To assess the effect of sildenafil, a phosphodiesterase type 5 inhibitor, on digital ulcer (DU) healing in systemic sclerosis (SSc). Methods Randomised, placebo-controlled study in patients with SSc to assess the effect of sildenafil 20 mg or placebo, three times daily for 12 weeks, on ischaemic DU healing. The primary end point was the time to healing for each DU. Time to healing was compared between groups using Cox models for clustered data (two-sided tests, p=0.05). Results Intention-to-treat analysis involved 83 patients with a total of 192 DUs (89 in the sildenafil group and 103 in the placebo group). The HR for DU healing was 1.33 (0.88 to 2.00) (p=0.18) and 1.27 (0.85 to 1.89) (p=0.25) when adjusted for the number of DUs at entry, in favour of sildenafil. In the per protocol population, the HRs were 1.49 (0.98 to 2.28) (p=0.06) and 1.43 (0.93 to 2.19) p=0.10. The mean number of DUs per patient was lower in the sildenafil group compared with the placebo group at week (W) 8 (1.23±1.61 vs 1.79±2.40 p=0.04) and W12 (0.86±1.62 vs 1.51±2.68, p=0.01) resulting from a greater healing rate (p=0.01 at W8 and p=0.03 at W12). Conclusions The primary end point was not reached in intention-to-treat, partly because of an unexpectedly high healing rate in the placebo group. We found a significant decrease in the number of DUs in favour of sildenafil compared with placebo at W8 and W12, confirming a sildenafil benefit. Trial registration number NCT01295736. PMID:25995322

Sildenafil (Viagra) prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current.

PubMed

Geelen, P; Drolet, B; Rail, J; Bérubé, J; Daleau, P; Rousseau, G; Cardinal, R; O'Hara, G E; Turgeon, J

2000-07-18

BACKGROUND-Several cases of unexpected death have been reported with sildenafil in patients predisposed to ischemic cardiac events. Although acute episodes of ischemia could account for some of these deaths, we hypothesized that sildenafil may have unsuspected electrophysiological effects predisposing some patients to proarrhythmia. METHODS AND RESULTS-Studies were undertaken in 10 isolated guinea pig hearts that demonstrated prolongation of cardiac repolarization in a reverse use-dependent manner by sildenafil 30 mcmol/L. Action potential duration increased 15% from baseline 117+/-3 to 134+/-2 ms with sildenafil during pacing at 250 ms cycle length, whereas a 6% increase from 99+/-2 to 105+/-2 ms was seen with pacing at 150 ms cycle length. Experiments in human ether-a-go-go-related gene (HERG)-transfected HEK293 cells (n=30) demonstrated concentration-dependent block of the rapid component (I(Kr)) of the delayed rectifier potassium current: activating current was 50% decreased at 100 mcmol/L. This effect was confirmed using HERG-transfected Chinese hamster ovary (CHO) cells, which exhibit no endogenous I(K)-like current. CONCLUSIONS-Sildenafil possesses direct cardiac electrophysiological effects similar to class III antiarrhythmic drugs. These effects are observed at concentrations that may be found in conditions of impaired drug elimination such as renal or hepatic insufficiency, during coadministration of another CYP3A substrate/inhibitor, or after drug overdose and offer a new potential explanation for sudden death during sildenafil treatment.

Effect of sildenafil citrate on endometrial preparation and outcome of frozen-thawed embryo transfer cycles: a randomized clinical trial.

PubMed

Dehghani Firouzabadi, Razieh; Davar, Robab; Hojjat, Farzaneh; Mahdavi, Mohamad

2013-02-01

Sildenafil citrate may increase endometrial thickness and affect the outcome of frozen-thawed embryo transfer cycles. The aim of this study was to estimate the effect of sildenafil citrate on ultrasonographic endometrial thickness and pattern and to investigate the estrogen level on the day of progesterone administration, the implantation rate and chemical pregnancy rate in frozen embryo transfer cycles. This randomized controlled trial was conducted on 80 patients who had an antecedent of poor endometrial response and frozen embryos. 40 patients were given estradiol by a step up method with menstruation to prepare the endometrium, and the other 40 were given sildenafil citrate tablets (50 mg) daily in addition to the above treatment protocol from the first day of the cycle until the day progesterone was started. This was discontinued 48-72 hours prior to the embryo transfer. The endometrial thickness was significantly higher in the sildenafil citrate group (p<0.0001), the triple line patterns of the endometrium were significantly higher in the sildenafil citrate group (p<0.0001), while the intermediate patterns of the endometrium were not significantly different in the two groups. The echogen patterns of the endometrium were significantly higher in control group (p<0.0001). Finally, implantation rate and the chemical pregnancy rates were higher in the sildenafil citrate group but not significantly. As our study shows, the oral use of sildenafil citrate is a good way to improve the endometrial receptivity. We recommend the routine use of oral sildenafil citrate in patients with a previous failure of assisted reproduction technology cycles due to poor endometrial thickness.

Effectiveness and Safety of Oro-Dispersible Sildenafil in a New Film Formulation for the Treatment of Erectile Dysfunction: Comparison Between Sildenafil 100-mg Film-Coated Tablet and 75-mg Oro-Dispersible Film.

PubMed

Cocci, Andrea; Capece, Marco; Cito, Gianmartin; Russo, Giorgio Ivan; Falcone, Marco; Timpano, Massimiliano; Rizzo, Michele; Della Camera, Pier Andrea; Morselli, Simone; Campi, Riccardo; Sessa, Francesco; Cacciamani, Giovanni; Minervini, Andrea; Gacci, Mauro; Mirone, Vincenzo; Morelli, Girolamo; Mondaini, Nicola; Polloni, Gaia; Serni, Sergio; Natali, Alessandro

2017-12-01

A new oro-dispersible film (ODF) formulation of sildenafil has been developed for the treatment of erectile dysfunction (ED) to overcome the drawbacks that some patients experience when taking the conventional film-coated tablet (FCT). To assess the effectiveness and safety of sildenafil ODF formulation in patients with ED who were using the conventional FCT. From May 2017 through July 2017, 139 patients with ED were enrolled. Data from penile color-duplex ultrasound, medical history, hormonal evaluation, and patient self-administered questionnaires were collected. All patients were administered sildenafil 100-mg FCT for 4 weeks. Thereafter, they underwent a 2-week washout period and subsequently took sildenafil 75-mg ODF for 4 weeks. The International Index of Erectile Function (IIEF-15), Hospital Anxiety and Depression Scale (HADS), Patient Global Impressions of Improvement (PGI-I), and Clinician Global Impressions of Improvement (CGI-I) questionnaires were administered and severity of ED was classified as severe (IIEF-15 score ≤ 10), moderate (IIEF-15 score 11-16), or mild (IIEF-15 score = 17-25). All patients completed the final protocol. Differences in mean IIEF scores for erectile function, orgasmic function, sexual desire, and intercourse satisfaction were significantly in favor of sildenafil 100-mg FCT, whereas the mean score for overall satisfaction was in favor of sildenafil 75-mg ODF. A significant difference in changes in HADS score was found from washout to final follow-up (mean difference = -0.19; P < .01). For the ODF formulation, the median CGI-I score was 3.5 (interquartile range [IQR] = 2.5-4.5) and the median PGI-I score was 3.0 (IQR = 2.0-4.0). The median action time was 20.0 minutes (IQR = 15.0-30.0) and the median mouth time was 60.0 seconds (IQR = 30.0-120.0). The ODF formulation of a widely known drug, with the same safety and effectiveness of the FCT, was better appreciated by patients in overall satisfaction. This is the first

Treatment of antidepressant-associated sexual dysfunction with sildenafil: a randomized controlled trial.

PubMed

Nurnberg, H George; Hensley, Paula L; Gelenberg, Alan J; Fava, Maurizio; Lauriello, John; Paine, Susan

2003-01-01

Sexual dysfunction is a common adverse effect of antidepressants that frequently results in treatment noncompliance. To assess the efficacy of sildenafil citrate in men with sexual dysfunction associated with the use of selective and nonselective serotonin reuptake inhibitor (SRI) antidepressants. Prospective, parallel-group, randomized, double-blind, placebo-controlled trial conducted between November 1, 2000, and January 1, 2001, at 3 US university medical centers among 90 male outpatients (mean [SD] age, 45 [8] years) with major depression in remission and sexual dysfunction associated with SRI antidepressant treatment. Patients were randomly assigned to take sildenafil (n = 45) or placebo (n = 45) at a flexible dose starting at 50 mg and adjustable to 100 mg before sexual activity for 6 weeks. The primary outcome measure was score on the Clinical Global Impression-Sexual Function (CGI-SF); secondary measures were scores on the International Index of Erectile Function, Arizona Sexual Experience Scale, Massachusetts General Hospital-Sexual Functioning Questionnaire, and Hamilton Rating Scale for Depression (HAM-D). Among the 90 randomized patients, 93% (83/89) of patients treated per protocol took at least 1 dose of study drug and 85% (76/89) completed week 6 end-point assessments with last observation carried forward analyses. At a CGI-SF score of 2 or lower, 54.5% (24/44) of sildenafil compared with 4.4% (2/45) of placebo patients were much or very much improved (P<.001). Erectile function, arousal, ejaculation, orgasm, and overall satisfaction domain measures improved significantly in sildenafil compared with placebo patients. Mean depression scores remained consistent with remission (HAM-D score < or =10) in both groups for the study duration. In our study, sildenafil effectively improved erectile function and other aspects of sexual function in men with sexual dysfunction associated with the use of SRI antidepressants. These improvements may allow patients

Cardiovascular effects of sildenafil during exercise in men with known or probable coronary artery disease: a randomized crossover trial.

PubMed

Arruda-Olson, Adelaide M; Mahoney, Douglas W; Nehra, Ajay; Leckel, Marilyn; Pellikka, Patricia A

2002-02-13

The relationship between sildenafil citrate use and reported adverse cardiovascular events in men with coronary artery disease (CAD) is unclear. To evaluate the cardiovascular effects of sildenafil during exercise in men with CAD. Randomized, double-blind, placebo-controlled crossover trial conducted March to October 2000 at a US ambulatory-care referral center among 105 men with a mean (SD) age of 66 (9) years who had erectile dysfunction and known or highly suspected CAD. All patients underwent 2 symptom-limited supine bicycle echocardiograms separated by an interval of 1 to 3 days after receiving a single dose of sildenafil (50 or 100 mg) or placebo 1 hour before each exercise test. Hemodynamic effects of sildenafil during exercise (onset, extent, and severity of ischemia) assessed by exercise echocardiography. Mean (SD) resting ejection fraction was 56% (7%) (range, 39%-68%). After sildenafil use, resting systolic blood pressure was reduced from 135 (19) mm Hg to 128 (17) mm Hg, for a mean change of -7 mm Hg (95% confidence interval [CI], -9 to -4 mm Hg; P<.001). After placebo use, the mean (SD) change was from 135 (20) mm Hg to 133 (19) mm Hg, a difference of -2 mm Hg (95% CI, -6 to 0.3 mm Hg; P =.08). The difference between mean change after sildenafil and placebo use was 4.3 (95% CI, 0.9-7.7; P =.01). Resting heart rate, diastolic blood pressure, and wall motion score index (a measure of the extent and severity of wall motion abnormalities) did not change significantly in either group. Exercise capacity was similar with sildenafil use (mean [SD], 4.5 [1.0] metabolic equivalents) and placebo use (mean [SD], 4.6 [1.0] metabolic equivalents; mean difference, 0.07; 95% CI, -.06 to 0.19; P =.29). Exercise blood pressure and heart rate increments were similar. Dyspnea or angina developed in 69 patients who took sildenafil and 70 patients who took placebo (P =.89); exercise electrocardiography was positive in 12 patients (11%) who took sildenafil and 17 patients

Development and evaluation of an immunochromatographic strip for rapid screening of sildenafil-type compounds as illegal additives in functional foods.

PubMed

Guo, Jiebiao; Liu, Wangpei; Lan, Xianquan; Chen, Hualong; Xiao, Zijun

2016-07-01

Sildenafil is a phosphodiesterase-5 inhibitor (PDE-5) for the treatment of erectile dysfunction. Undeclared sildenafil and related analogues adulterated in functional foods are a threat to public health. To screen these illegal drugs rapidly in herbal samples, an immunochromatographic (IC) assay was developed based on polyclonal antibodies specific to both sildenafil and its analogues. A group that is pharmacological necessary for sildenafil and its analogues was employed as a representative hapten for the generation antibodies against the target compounds. The desired antisera showed satisfactory specificities to sildenafil and major analogues with IC50 values ranging from 19.3 to 34.6 ng ml(-1) in a referring enzyme-linked immunosorbent assay (ELISA). The optimised IC assay showed detection thresholds in the range 5.0-20 μg g(-1) for sildenafil and major analogues in herbal samples. Sixty herbal food supplements were screened and six were found to be positive using the IC strip. It was confirmed by ELISA and UPLC-PDA-MS/MS that positive samples contain target illegal additives in levels of 10-40 mg g(-1) (1-4%). In this range, sensitivity of the IC strip is adequate to screen sildenafil-type compounds in herbal commodities under a dilution ratio of 1:10(3). Thus, the current IC assay is a suitable tool for screening sildenafil and its analogues as illegal additives in herbal food supplements.

Treatment response to sildenafil in men with erectile dysfunction relative to concomitant comorbidities and age.

PubMed

Goldstein, Irwin; Stecher, Vera; Carlsson, Martin

2017-03-01

To evaluate treatment response in men with erectile dysfunction (ED) and concomitant comorbidities. Data were pooled from 42 placebo-controlled, flexible-dose sildenafil trials. In most trials, the sildenafil dose was 50 mg, taken ~1 hour before sexual activity but not more than once daily, with adjustment to 100 or 25 mg as needed. The overall population (N=9413) was stratified by age (<45, 46-64, ≥65 years). Treatment response was defined as a minimal clinically important difference (MCID) from baseline in the International Index of Erectile Function-Erectile Function (IIEF-EF) domain score of >2, >5 and >7 for men with mild, moderate and severe ED at baseline, respectively, or an IIEF-EF domain score ≥26 (no ED) at end-point. In the overall population, treatment response using the IIEF-EF MCID definition was significantly greater (P<.0001) with sildenafil vs placebo in men with no comorbidity (77% vs 33%), cardiovascular disease/hypertension only (71% vs 27%), diabetes only (63% vs 24%) or depression only (78% vs 29%). Using an IIEF-EF score ≥26, treatment response was significantly greater (P<.0001) with sildenafil vs placebo in men with no comorbidity (49% vs 17%), cardiovascular disease/hypertension only (48% vs 12%), diabetes only (40% vs 12%) or depression only (60% vs 17%). With each definition, the treatment response for each age and comorbidity was significantly greater (P≤.0065) with sildenafil vs placebo. The treatment response was significantly greater with sildenafil vs placebo in men with ED and each comorbidity regardless of age. © 2017 John Wiley & Sons Ltd.

First-generation phosphodiesterase type 5 inhibitors dropout: a comprehensive review and meta-analysis.

PubMed

Corona, G; Rastrelli, G; Burri, A; Serra, E; Gianfrilli, D; Mannucci, E; Jannini, E A; Maggi, M

2016-11-01

The discontinuation rate with phosphodiesterase type 5 inhibitors (PDE5i) remains very high. The aim of this study was to review and meta-analyze currently available data regarding dropout of the first-generation of PDE5i including sildenafil, vardenafil, and tadalafil. An extensive Medline Embase and Cochrane search was performed including the following words: 'PDE5i', 'discontinuation'. All observational studies reporting the dropout rate of PDE5i and its specific causes without any arbitrary restrictions were included. Out of 103 retrieved articles, 22 were included in the study. Retrieved trials included a total of 162,936 patients with a mean age of 58.8 ± 7.9 years. Prevalence of reported comorbid diabetes and hypertension were 27.7% and 36.9%, respectively. PDE5i were associated with a mean discontinuation rate of 4% per month (almost 50% after one year). This rate was higher in younger subjects and in those reporting a higher prevalence of associated morbidities. Six main reasons of PDE5i dropout were identified in the evaluated trials. Partner-related problems and lack of efficacy represented the most important reasons for PDE5i discontinuation, although no significant difference among factors was detected. In conclusion, despite their high efficacy and easy administration, the discontinuation rate and dissatisfaction with PDE5i are still very high. Our data showed that no single factor plays a major role in PDE5i dropout, suggesting that the discontinuation rate is usually because of a combination of both medical problems and psychosocial and relational factors. © 2016 American Society of Andrology and European Academy of Andrology.

When “Chems” Meet Sex: A Rising Phenomenon Called “ChemSex”

PubMed Central

Giorgetti, Raffaele; Tagliabracci, Adriano; Schifano, Fabrizio; Zaami, Simona; Marinelli, Enrico; Busardò, Francesco Paolo

2017-01-01

Background: The term “chemsex” was coined to indicate the voluntary intake of psychoactive and non psychoactive drugs in the context of recreational settings to facilitate and/or to enhance sexual intercourses mostly among men who have sex with other men (MSM). Objective: The authors aimed to review the mechanisms of action, the toxicity and the pattern of use and abuse of substances involved in “chemsex” practice together with the sociocultural background underlying it and the health-related consequences that they may have. Results: Gamma-hydroxybutyrate, gamma-butyrolactone,1,4-butanediol, mephedrone, methamphetamine, sildenafil, tadalafil, vardenafil and alkyl nitrites have been described in their role of “chemsex drugs” including pharmacological action and in their implication to impair capacities to chose sexual partners and consensual sex. Moreover, it has been demonstrated that sexual activity over protracted length of time under the influence of chemsex drugs can result in rectal trauma or penile abrasions and a significant increase of the risk of transmission of sexual transmitted diseases, especially in case of condomless intercourses, which are frequent in this context, representing therefore a serious health threat. Conclusion: One of the major problems to establish health policy priority interventions for chemsex is the lack of available epidemiological data on the issue. Finally, social actions should be taken in order to break down the barriers that currently exist among chemsex drug users in accessing services, including the shame and stigma often associated with drug use. In conclusion, more specific resources to face high risks of infections and HIV transmission are required in bisexual and homosexual individuals having SUID: sex under the influence of drugs. PMID:27855594

The Phosphodiesterase 5-Inhibitors (PDE-5i) for ERECTILE DYSFUNCTION (ED): A Therapeutic Challenge For Psychiatrists.

PubMed

Koon, Chong Siew; Sidi, Hatta; Kumar, Jaya; Das, Srijit; Xi, Ong Wan; Hatta, Muhammad Hizri; Alfonso, Cesar

2017-02-15

Erectile function (EF) is a prerequisite for satisfactory sexual intercourse (SI) and central to male sexual functioning. Satisfactory SI eventually leads to orgasm - a biopsychophysiological state of euphoria - leading to a sense of bliss, enjoyment and positive mental well being. For a psychiatrist, treating ED is self-propelled to harmonize these pleasurable experiences alongside with encouragement of physical wellness and sensuality. Hence, the role of PDE-5i is pivotal in the context of treating ED constitutes a therapeutic challenge. PDE-5i work via the dopaminergic-oxytocin-nitric oxide pathway by increasing the availability of endothelial's guanosine monophosphate (GMP), immediately causing relaxation of the penile smooth muscle and an erection. The PDE-5i, like sildenafil, vardenafil and tadalafil, are effective in the treatment of ED with some benefits and disadvantages compared to other treatment modalities. Prescribed PDE-5i exclusively improve EF, fostering male's self-confidence and self-esteem. Treatment failures are associated with factors such as absent (or insufficient) sexual stimulation, psychosexual conflicts and the co-existence of medical disorders. Managing ED requires dealing with underlying medical diseases, addressing other co-morbid sexual dysfunctions like premature ejaculation (PE), and educating the patient on healthy life-styles beside being cautious with the potential side-effects and drug-drug interactions. Furthermore, by dealing with interpersonal dynamics within the couple and embracing adequate lifestyles (managing stress and revising one's sexual scripts), PDE-5i treatment benefits may be enhanced. In this review, we propose a holistic conceptual framework approach for psychiatric management of patients with ED. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Chronic vardenafil treatment improves erectile function via structural maintenance of penile corpora cavernosa in rats with acute arteriogenic erectile dysfunction.

PubMed

Hotta, Yuji; Hattori, Mayuko; Kataoka, Tomoya; Ohno, Risa; Mikumo, Mayumi; Maeda, Yasuhiro; Kimura, Kazunori

2011-03-01

Chronic phosphodiesterase type 5 inhibitor treatment may be useful in reversing erectile dysfunction (ED). However, the mechanisms of this improvement remain unknown. The aim of this article was to determine the mechanisms of the improvement by chronic vardenafil treatment for acute arteriogenic ED in rats. Eight-week-old male Wistar-ST rats were divided into four groups: sham-operated rats (Control group) and rats with acute arteriogenic ED induced by ligating bilateral internal iliac arteries (Ligation group), subsequently treated with low-dose (0.4 mg/kg/day; VL group) or high-dose (4.0 mg/kg/day; VH group) vardenafil for 20 days from 1 week after ligature. Erectile function was assessed based on changes of intracavernous pressure (ICP) followed by electrostimulation of the cavernous nerves and was evaluated by the area under the curve of ICP/area under the curve of mean arterial pressure (area of ICP/MAP). Transforming growth factor (TGF)-β(1), vascular endothelial growth factor-A, endothelial nitric oxide synthase (eNOS), inducible NOS, and neuronal NOS mRNA expression levels in penile corpus cavernosum were determined by real-time PCR. Western blotting for TGF-β(1) protein levels and Masson trichrome staining of penile tissues were performed in each at group 4 weeks after surgery. In the VH group, area of ICP/MAP was significantly improved when compared with the Ligation group (P < 0.01). The smooth muscle (SM)/collagen ratio in the VH group was significantly higher than in the Ligation group (P < 0.05), and was comparable with that in the Control group. TGF-β(1) mRNA and protein levels in the VH group were significantly lower when compared with the Ligation group (P < 0.05). Chronic vardenafil administration ameliorates impairment of penile hemodynamics and maintains normal SM to collagen ratio in cavernous tissues after acute arterial injury in rats. © 2010 International Society for Sexual Medicine.

Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial.

PubMed

Simonneau, Gérald; Rubin, Lewis J; Galiè, Nazzareno; Barst, Robyn J; Fleming, Thomas R; Frost, Adaani E; Engel, Peter J; Kramer, Mordechai R; Burgess, Gary; Collings, Lorraine; Cossons, Nandini; Sitbon, Olivier; Badesch, David B

2008-10-21

Oral sildenafil and intravenous epoprostenol have independently been shown to be effective in patients with pulmonary arterial hypertension. To investigate the effect of adding oral sildenafil to long-term intravenous epoprostenol in patients with pulmonary arterial hypertension. A 16-week, double-blind, placebo-controlled, parallel-group study. Multinational study at 41 centers in 11 countries from 3 July 2003 to 27 January 2006. 267 patients with pulmonary arterial hypertension (idiopathic, associated anorexigen use or connective tissue disease, or corrected congenital heart disease) who were receiving long-term intravenous epoprostenol therapy. Patients were randomly assigned to receive placebo or sildenafil, 20 mg three times daily, titrated to 40 mg and 80 mg three times daily, as tolerated, at 4-week intervals. Of 265 patients who received treatment, 256 (97%) patients (123 in the placebo group and 133 in the sildenafil group) completed the study. Change from baseline in exercise capacity measured by 6-minute walk distance (primary end point) and hemodynamic measurements, time to clinical worsening, and Borg dyspnea score (secondary end points). A placebo-adjusted increase of 28.8 meters (95% CI, 13.9 to 43.8 meters) in the 6-minute walk distance occurred in patients in the sildenafil group; these improvements were most prominent among patients with baseline distances of 325 meters or more. Relative to epoprostenol monotherapy, addition of sildenafil resulted in a greater change in mean pulmonary arterial pressure by -3.8 mm Hg (CI, -5.6 to -2.1 mm Hg); cardiac output by 0.9 L/min (CI, 0.5 to 1.2 L/min); and longer time to clinical worsening, with a smaller proportion of patients experiencing a worsening event in the sildenafil group (0.062) than in the placebo group (0.195) by week 16 (P = 0.002). Health-related quality of life also improved in patients who received combined therapy compared with those who received epoprostenol monotherapy. There was no

Sildenafil improves clinical signs and radiographic features in dogs with congenital idiopathic megaoesophagus: a randomised controlled trial.

PubMed

Quintavalla, F; Menozzi, A; Pozzoli, C; Poli, E; Donati, P; Wyler, D K; Serventi, P; Bertini, S

2017-04-22

We evaluated the efficacy of oral sildenafil citrate in dogs with congenital idiopathic megaoesophagus (CIM). Twenty-one puppies were randomly assigned to two groups (treatment and control). The dogs were given sildenafil oral suspension 1 mg/kg every 12 hours for 14 days or placebo in a masked fashion. Clinical signs (frequency of regurgitation and weight gain) and oesophagrams (relative oesophageal diameter, ROD) were evaluated in order to assess the efficacy of drug treatment, by examiners who were unaware of the study protocol. In addition, a set of in vitro experiments on isolated samples of canine lower oesophageal sphincter (LOS) was performed, and the effects of increasing concentrations of sildenafil on basal tone and electrically-stimulated motility were assessed. Sildenafil administration significantly reduced the number of regurgitation episodes (0.88±1.40 v 2.65±1.56, P<0.0001) and significantly increased weight gain in the treated dogs compared to controls (79.76±28.30 per cent v 53.40±19.30 per cent, P=0.034). ROD values, at the end of the treatment period, were significantly decreased in the sildenafil group, compared to pre-treatment values (0.97±0.19 v 0.24±0.14, P<0.0001), in contrast to control subjects (0.98±0.17 v 1.10±0.25, P=0.480). In accordance with the in vivo findings, sildenafil dose-dependently reduced basal tone and increased electrically-induced relaxation of dog LOS samples. These results suggest that sildenafil citrate helps ameliorate clinical and radiographic signs in dogs with CIM by reducing LOS tone, and could represent a novel therapeutic tool for the treatment of this disease. British Veterinary Association.

Chronic administration of sildenafil improves erectile function in a rat model of chronic renal failure

PubMed Central

Gurbuz, Nilgun; Kol, Arif; Ipekci, Tumay; Ates, Erhan; Baykal, Asli; Usta, Mustafa F

2015-01-01

The relationship between erectile dysfunction (ED) and chronic renal failure (CRF) has been reported in several studies. This study aimed to investigate whether the chronic use of sildenafil could enhance the erectile capacity in CRF-induced rats. In addition, we assessed the effect of that treatment on certain molecules, which have been suggested to play crucial roles in erectile physiology and CRF-related ED as well. Three groups of animals were utilized: (1) age-matched control rats, (2) CRF-induced rats, (3) CRF-induced rats treated with chronic administration of sildenafil (5 mg kg−1 p.o. for 6 weeks [treatment started after 6 weeks of CRF induction]). At 3 months, all animals underwent cavernosal nerve stimulation (CNS) to assess erectile function. Penile tissue advanced glycation end products (AGE's)/5-hydroxymethyl-2-furaldehyde, malondialdehyde (MDA), cGMP (ELISA), inducible nitric oxide synthase (iNOS) and neuronal NOS (nNOS) (Western blot) analyses were performed in all rat groups. CRF-induced rats had a significant decrease in erectile function when compared to control rats (P < 0.05). The increase in both intracavernosal pressure (ICP) and area under the curve of CRF-induced rats treated with sildenafil (Group 3) was greater than CRF-induced rats (Group 2). Additionally, sildenafil treatment decreased AGE, MDA and iNOS levels, while it preserved nNOS and cGMP contents in CRF-induced penile tissue. Decreased AGE, MDA, iNOS and increased nNOS, cGMP levels at the sildenafil-treated group increased both ICP and Total ICP to CNS, which led to improve erectile function in CRF-induced rats. The results of the present study revealed the therapeutic effect of chronic sildenafil administration on erectile function in CRF-induced rats. PMID:25652632

Pharmacist supply of sildenafil: pharmacists' experiences and perceptions on training and tools for supply.

PubMed

Braund, Rhiannon; Ratnayake, Kaushalya; Tong, Katie; Song, Jackie; Chai, Stephen; Gauld, Natalie

2018-06-01

Background In 2014, New Zealand reclassified sildenafil (for erectile dysfunction) to allow supply by specially trained pharmacists under strict criteria. Objective The study aimed to determine pharmacists' experiences and perspectives on the training for, and supply of sildenafil under this model. Setting New Zealand community pharmacy. Method This qualitative study captured data with a semi-structured interview used with purposively-sampled participants. A maximum variation sample was used to select a wide range of pharmacists working in various pharmacies, including pharmacists who were trained to provide sildenafil and those not trained to supply sildenafil. Consenting pharmacists were interviewed, with interviews audio-recorded and transcribed. Analysis used a framework approach. Main outcome measures Topics explored included: satisfaction and experience of the training; suitability and usability of the screening tools; experiences of the supply process and why some pharmacists chose not to become trained. Results Thirty-five pharmacists were interviewed. Training was seen as uncomplicated and the screening tools provided confidence that key consultation areas were covered. Most consultations reportedly took 15-20 min, some up to 60 min. Pharmacists reported being comfortable with the consultations. Many men requesting supply fell outside of the parameters, resulting in medical referral. This new model of supply was seen as a positive for pharmacists and their patients. Unaccredited pharmacists reported a perceived lack of interest from men, or ability to provide the service as reasons for not seeking accreditation. Conclusion New Zealand's model of pharmacist supply of sildenafil appears workable with some areas for improvement identified.

Beliefs and social norms about sildenafil citrate (Viagra) misuse and perceived consequences among Houstonian teenage males.

PubMed

Peters, Ronald J; Johnson, Regina J; Kelder, Steve; Meshack, Angela F; Jefferson, Troy

2007-09-01

In the current study, a qualitative approach was used to investigate relevant beliefs and norms associated with sildenafil citrate (Viagra) consumption, initiation, and perceived consequences. Focus groups were conducted with 43 young men aged 18 and 19 years who identified themselves as lifetime sildenafil citrate users. The majority of focus group participants believed that "curiosity" and "peer pressure" contributed to their initial use. Most revealed that they first heard about sildenafil citrate from television advertisements, family members, friends, or sporting events, and they were able to obtain the drug from their friends and family members or they stole it from their father or grandfather. These findings may highlight the relative importance of exposure to prescription drug messages among those to whom the message is not specifically targeted, that is, young men. It is possible that the sildenafil citrate television messages are recalled by not only older male audiences but also by teenagers and younger men, producing similar cognitive processing and curiosity in both age cohorts.

Sildenafil Protects against Myocardial Ischemia-Reperfusion Injury Following Cardiac Arrest in a Porcine Model: Possible Role of the Renin-Angiotensin System

PubMed Central

Wang, Guoxing; Zhang, Qian; Yuan, Wei; Wu, Junyuan; Li, Chunsheng

2015-01-01

Sildenafil, a phosphodiesterase-5 inhibitor sold as Viagra, is a cardioprotector against myocardial ischemia/reperfusion (I/R) injury. Our study explored whether sildenafil protects against I/R-induced damage in a porcine cardiac arrest and resuscitation (CAR) model via modulating the renin-angiotensin system. Male pigs were randomly divided to three groups: Sham group, Saline group, and sildenafil (0.5 mg/kg) group. Thirty min after drug infusion, ventricular fibrillation (8 min) and cardiopulmonary resuscitation (up to 30 min) was conducted in these animals. We found that sildenafil ameliorated the reduced cardiac function and improved the 24-h survival rate in this model. Sildenafil partly attenuated the increases of plasma angiotensin II (Ang II) and Ang (1–7) levels after CAR. Sildenafil also decreased apoptosis and Ang II expression in myocardium. The increases of expression of angiotensin-converting-enzyme (ACE), ACE2, Ang II type 1 receptor (AT1R), and the Ang (1–7) receptor Mas in myocardial tissue were enhanced after CAR. Sildenafil suppressed AT1R up-regulation, but had no effect on ACE, ACE2, and Mas expression. Sildenafilfurther boosted the upregulation of endothelial nitric oxide synthase (eNOS), cyclic guanosine monophosphate (cGMP) and inducible nitric oxide synthase(iNOS). Collectively, our results suggest that cardioprotection of sildenafil in CAR model is accompanied by an inhibition of Ang II-AT1R axis activation. PMID:26569234

The effects of sildenafil citrate (Viagra) on uterine blood flow and well being in the intrauterine growth-restricted fetus.

PubMed

Miller, Suzanne L; Loose, Jan M; Jenkin, Graham; Wallace, Euan M

2009-01-01

This study examined whether the type-5 phosphodiesterase inhibitor sildenafil citrate (Viagra; Pfizer, New York, NY) could increase uterine blood flow in intrauterine growth restriction (IUGR), thereby improving fetal oxygenation and well being. In fetal sheep, we induced IUGR at 105-110 days (0.7 gestation) using single umbilical artery ligation (SUAL). In SUAL and control animals, we measured uterine blood flow (UBF) and blood gases before and after sildenafil administration. SUAL fetuses were hypoxemic compared with controls. Following sildenafil, UBF was significantly decreased in both SUAL and control ewes for approximately 40 minutes. In response to sildenafil, pO(2) was decreased in SUAL and control fetuses and both groups displayed significant hypotension and tachycardia. At postmortem SUAL fetal body weight was significantly reduced by 23% compared with controls. Sildenafil does not improve UBF or fetal well being in SUAL-induced IUGR pregnancies and should be used with caution in IUGR and healthy pregnancies because of its detrimental effects on uteroplacental perfusion and on the fetus.

A population pharmacokinetic analysis of sildenafil citrate in patients with erectile dysfunction

PubMed Central

Milligan, Peter A; Marshall, Scott F; Karlsson, Mats O

2002-01-01

Aims To analyse the pharmacokinetics of sildenafil citrate in patients with erectile dysfunction in order to characterize covariate relationships and assist in the development of rational dosage strategies. Methods A population pharmacokinetic sampling strategy was incorporated into five phase III clinical study protocols. Overall, 2077 patients, 1335 of whom received sildenafil, were asked to take an additional dose of study drug before their scheduled clinic visits on four or five occasions throughout the study duration. A single plasma sample was obtained at random times postdose (range 1–7 h), and a total of 4582 samples were assayed (average 3.4 samples per individual). Results For the population average patient (age 58 years; aspartate transaminase [AST], 24 IU l−1; weight, 87 kg; not receiving CYP3A4 potential inhibitors), typical values for sildenafil (mean±SE) were 58.5±1.4 l h−1 for apparent clearance (CL/F), 310±6.92 l for volume of distribution (V/F), and 2.6±0.176 h−1 for first-order absorption constant (ka). The value for ka is associated with meal consumption within 2 h predose, at all other times ka was equivalent to an instantaneous bolus administration. The interindividual variabilities were 29% for CL/F, 20% for V/F, and 210% for ka. Over a dose range of 25–100 mg sildenafil, the pharmacokinetics exhibited dose proportionality. There was evidence of nonproportionality (40% increase on average) in relative bioavailability with respect to the 200-mg dose (P < 0.001) relative to the other doses. Age, AST concentration, and co-administration with CYP3A4 potential inhibitors significantly influenced CL/F of sildenafil (P < 0.001, for each relationship). For age and AST, the extent of the linear relationships (extrapolated from population average values) included a 4% decrease in CL/F for every decade increase and a 6% decrease in CL/F for every 10-unit increase, respectively. Following co-administration of CYP3A4 potential inhibitors, a

Sildenafil citrate as a medical expulsive therapy for distal ureteric stones: A randomised double-blind placebo-controlled study.

PubMed

Shokeir, Ahmed A; Tharwat, Mohamed A; Abolazm, Ahmed Elhussein; Harraz, Ahmed

2016-03-01

To study the effect of sildenafil citrate on spontaneous passage of distal ureteric stones (DUS). This was a randomised double-blinded placebo-controlled study of 100 patients with DUS. Inclusion criteria were: male, age 18-65 years, normal renal function, and a single radiopaque unilateral DUS of 5-10 mm. Patients were randomly allocated into two equal groups, one that received placebo and the other that received 50 mg sildenafil citrate once daily. Both investigators and patients were masked to the type of treatment. Patients self-administered the medication until spontaneous passage of the DUS. In patients where there was uncontrolled pain, fever, an increase in serum creatinine of >1.8 mg/dL, progressive hydronephrosis or no further progress after 4 weeks, a decision was taken for further treatment. In all, 47 and 49 patients were available for analysis in both the placebo and sildenafil citrate groups; respectively. Both groups were comparable for age and stone characteristics. Spontaneous expulsion occurred in 19 of 47 patients (40.4%) in the placebo group and in 33 of 49 (67.3%) in the sildenafil citrate group (P = 0.014). The mean time to stone expulsion was significantly shorter in the sildenafil citrate group (P < 0.001). A multivariable Cox proportional hazards model showed that receiving sildenafil citrate was the only independent factor that had a significant impact on stone passage with a hazard ratio of 2.7 (95% confidence interval 1.5-4.8; P < 0.001). Sildenafil citrate enhances spontaneous passage of 5-10 mm DUS.

Health care cost implications of sildenafil citrate.

PubMed

Miner, Martin

2004-09-01

As prescription drug expenditures increase, third-party payors are increasingly scrutinizing costs and reimbursement guidelines, such as for medications that treat chronic conditions that are not necessarily directly life threatening (i.e., obesity, nicotine addiction, and erectile dysfunction). To review the costs and consequences of pharmacy benefit reimbursement policies related to erectile dysfunction therapies, using sildenafil citrate as the case study. Data and references were found through searches of PubMed and Google. To meet the varied health needs of a defined population under reasonable resource constraints requires analysis of cost and of the economic and non-economic consequences of a treatment. Based on analysis of sildenafil data, oral therapy of erectile dysfunction provides substantial cost savings when compared with other treatment options and contributes insignificant overall costs to health plans. Regardless, health plans impose controls to limit reimbursement. Because erectile dysfunction is often a precursor to other conditions, such limitations could compromise detection and management of underlying disease (e.g., depressive, cardiovascular, and urogenital). Reimbursement restrictions may also decrease membership satisfaction and re-enrollment rates.

Comparison of Elaeagnus angustifolia Extract and Sildenafil Citrate on Female Orgasmic Disorders: A Randomized Clinical Trial.

PubMed

Akbarzadeh, Marzieh; Zeinalzadeh, Sanaz; Zolghadri, Jaleh; Mohagheghzadeh, Abdolali; Faridi, Pouya; Sayadi, Mehrab

2014-10-01

Orgasmic disorder can create a feeling of deprivation and failure and provide mental problems, incompatibility and marital discord. This study aimed to compare the effects of Elaeagnus angustifolia flower extract and sildenafil citrate on female orgasmic disorder in women in 2013. In this randomized clinical trial, 125 women between 18-40 years old who suffered from orgasmic disorder were divided into three E. angustifolia, sildenafil citrate and control groups. The data were gathered using Female Sexual Function Index and through measurement of TSH and prolactin. The first intervention group had to consume 4.5 gr E. angustifolia extract in two divided doses for 35 days and the second one had to use 50 mg sildenafil citrate tablets for 4 weeks one hour before their sexual relationship. However, the control group had to consume the placebo. The data were analyzed using paired t-test, one-way ANOVA, and Bonferroni posthoc test and p<0.05 was considered significant. The frequency of orgasmic disorder before the intervention was 41.5%, 40.5%, and 57.1% in E. angustifolia, sildenafil citrate, and control groups, respectively (p=0.23). However, these measures were respectively 29.3%, 16.7%, and 50% after the intervention (p=0.004). A significant difference between the two groups regarding sexual satisfaction after the intervention (p=0.003) compared to the beginning of the study (p=0.356). Besides, the highest reduction of changes after the intervention (58.82%) was observed in the sildenafil citrate group. Both E. angustifolia extract and sildenafil citrate were effective in reduction of the frequency of orgasmic disorder in women.

Community-based study of erectile dysfunction and sildenafil use: the Rancho Bernardo study.

PubMed

Monga, Manoj; Bettencourt, Ricki; Barrett-Connor, Elizabeth

2002-05-01

To evaluate erectile dysfunction (ED) using a validated self-administered 5-item questionnaire (5-item version of the International Index of Erectile Function [IIEF-5]) and the use of sildenafil in community-dwelling older men. In October 1998, the IIEF-5 was mailed to all surviving members of an established community-based cohort of older men. The degree of ED was stratified by the erectile function domain score as complete (4 or less), severe (5 to 10), moderate (11 to 14), mild (15 to 18), or none (19 to 20). Men were also asked about sildenafil use and its effectiveness. A total of 976 men (64%) responded to the questionnaire. The internal consistency of the questionnaire construct was confirmed, with a Cronbach's alpha coefficient of 0.96 for all 5 questions. Eighty-nine percent of men younger than 50 years were sexually active compared with 37% of men older than age 80. Twenty-six percent of sexually active men reported complete (3%), severe (10.5%), or moderate (12.6%) ED. The prevalence of moderate or complete ED increased with age and was reported by 58% of men aged 75 to 79 years. Eleven percent of sexually active men had used sildenafil one or more times, with 63% reporting good or "terrific" effects and 11% reporting no benefit. The response to sildenafil deteriorated with age and increasing degree of ED. The results of this community-based study confirm the strong correlation between advancing age and the prevalence and degree of ED, with 33% of men aged 75 and older reporting at least moderate ED. Nevertheless, more than 33% of men older than 75 years remained sexually active. Of the 660 sexually active men, 81% reported satisfaction with sexual intercourse; only 11% had tried sildenafil.

Intravenous sildenafil in right ventricular dysfunction with pulmonary hypertension following a heart transplant.

PubMed

Bonet, Luis Almenar; Guillén, Rosario Vicente; Lázaro, Ignacio Sánchez; de la Fuente, Carmen; Osseyran, Faisa; Dolz, Luis Martínez; Hernández, Mónica Montero; Sanz, Manuel Portolés; Otero, Miguel Rivera; Sanz, Antonio Salvador

2014-01-01

The objective of the present work is to describe the experience with intravenous (IV) sildenafil in heart transplant (HT) patients with reactive pulmonary hypertension (PH) who developed right ventricular dysfunction (RVD) in the immediate postoperative period. The first 5 patients who received IV sildenafil followinga HT are presented. The HTs took place between March 2011 and September 2012 in patients aged 37 to 64 years; all patients were male. Prior to the HT, mean pulmonary artery pressure (mPAP) was 32-56 mmHg. In all cases, the hemodynamic study demonstrated PH reactivity (positive vasodilator test with nitric oxide). All 5 patients developed RVD with hemodynamic instability immediately after the HT, despite the administration of nitric oxide from the time of intubation prior to the implant, optimal medical treatment in all cases, and a ventricular assist in 2 cases. In all patients, IV sildenafil was initiated at 10 mg/8 h for 48 h and was subsequently increased to 20 mg/8 h. in its oral formulation until discharge from the hospital. The change in pulmonary pressure was assessed using a Swan-Ganz catheter. Ventricular function was assessed using echocardiography. Length of stay in the Resuscitation Unit and mid-term survival were also assessed. Average time of extracorporeal circulation was 200 ± 110 min and organ ischemic time was 210 ± 95 min. All of the patients demonstrated pulmonary and systemic hemodynamic improvement, as well as recovery of right ventricular function after completing the treatment with IV sildenafil. The stay in the Resuscitation Unit lasted 3-25 days. All the patients were discharged from hospital with no mortality to date. Intravenous sildenafil improves right ventricle hemodynamics associated with pulmonary hypertension post-HT. Prophylactic prevention with this drug could be indicated for patients with reactive PH who are about to receive a transplant.

Effect of sildenafil on subjective and physiologic parameters of the female sexual response in women with sexual arousal disorder.

PubMed

Berman, J R; Berman, L A; Lin, H; Flaherty, E; Lahey, N; Goldstein, I; Cantey-Kiser, J

2001-01-01

Sexual dysfunction is a complaint of 30-50% of American women. Aside from hormone replacement therapy, there are no current FDA-approved medical treatments for female sexual complaints. The goal of this pilot study was to determine safety and efficacy of sildenafil for use in women with sexual arousal disorder (SAD). Evaluations were completed on 48 women with complaints of SAD. Physiologic measurements, including genital blood flow, vaginal lubrication, intravaginal pressure-volume changes, and genital sensation were recorded pre- and postsexual stimulation at baseline and following 100 mg sildenafil. Subjective sexual function was assessed using a validated sexual function inventory at baseline and following 6 weeks of home use of sildenafil. At termination of the study patients also completed an intervention efficacy index (FIEI). Following sildenafil, poststimulation physiologic measurements improved significantly compared to baseline. Baseline subjective sexual function complaints, including low arousal, low desire, low sexual satisfaction, difficulty achieving orgasm, decreased vaginal lubrication, and dyspareunia also improved significantly following 6 weeks home use of sildenafil. Sildenafil appears to significantly improve both subjective and physiologic parameters of the female sexual response. Double-blind, placebo-controlled studies are currently in progress to further determine efficacy of this medication for treatment of female sexual dysfunction complaints in different populations of women.

Evaluation of Pharmacokinetic and Pharmacodynamic Drug–Drug Interaction of Sacubitril/Valsartan (LCZ696) and Sildenafil in Patients With Mild‐to‐Moderate Hypertension

PubMed Central

Langenickel, TH; Petruck, J; Kode, K; Ayalasomayajula, S; Schuehly, U; Greeley, M; Pal, P; Zhou, W; Prescott, MF; Sunkara, G; Rajman, I

2017-01-01

Sacubitril/valsartan (LCZ696) is indicated for the treatment of patients with heart failure and reduced ejection fraction (HFrEF). Since patients with HFrEF may receive sacubitril/valsartan and sildenafil, both increasing cyclic guanosine monophosphate, the present study evaluated the pharmacokinetic and pharmacodynamic drug interaction potential between sacubitril/valsartan and sildenafil. In this open‐label, three‐period, single sequence study, patients with mild‐to‐moderate hypertension (153.8 ± 8.2 mmHg mean systolic blood pressure (SBP)) received a single dose of sildenafil 50 mg, sacubitril/valsartan 400 mg once daily for 5 days, and sacubitril/valsartan and sildenafil coadministration. When coadministered with sildenafil, the AUC and Cmax of valsartan decreased by 29% and 39%, respectively. Coadministration of sacubitril/valsartan and sildenafil resulted in a greater decrease in BP (–5/–4/–4 mmHg mean ambulatory SBP/DBP/MAP (mean arterial pressure)) than with sacubitril/valsartan alone. Both treatments were generally safe and well tolerated in this study; however, the additional BP reduction suggests that sildenafil should be administered cautiously in patients receiving sacubitril/valsartan. Unique identifier: NCT01601470. PMID:28599060

Synergistic effects of BAY 60-4552 and vardenafil on relaxation of corpus cavernosum tissue of patients with erectile dysfunction and clinical phosphodiesterase type 5 inhibitor failure.

PubMed

Albersen, Maarten; Linsen, Loes; Tinel, Hanna; Sandner, Peter; Van Renterghem, Koenraad

2013-05-01

Overall efficacy rates of phosphodiesterase type 5 inhibitors (PDE5-i) for erectile dysfunction (ED) are 60-70%. PDE5-i treatment failures currently have to resort to invasive treatment options for restoration of erectile function. AIMS.: To assess changes in the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)/protein kinase (PKG) pathway in human corpus cavernosum (HCC) of PDE5-i nonresponders compared with healthy controls. To evaluate the effects of BAY 60-4552, a stimulator of soluble guanylate cyclase (sGC), and vardenafil on relaxation of HCC strips from PDE5-i nonresponders. mRNA expression, morphological localization of the NO/cGMP/PKG pathway, and relaxant capacity of both compounds alone or combined. Analysis of variance, t-test or Mann-Whitney test based upon number of groups and normality of data. HCC tissues were harvested after consent from individuals undergoing penile prosthesis implantation (patients) and potent patients undergoing transurethral surgery (healthy controls, needle biopsy). HCC tissues of patients were compared with those of healthy controls for the expression of mRNA coding for PDE5A, eNOS, PKGα1, PKG2, sGCα1, sGCα2, sGCβ1, sGCβ2, α-smooth muscle actin (aSMA) and β-actin by quantitative polymerase chain reaction (qPCR). The respective proteins were localized using immunofluorescence. Tissue strips of patients were precontracted with phenylepinephrine followed by incubation with 1 μM of either vardenafil or BAY 60-4552, or both simultaneously. The main targets in the NO/cGMP/sGC pathway were downregulated in PDE5-i nonresponders. The pathway was morphologically located to HCC smooth muscle, of which the overall content was preserved in ED patients based on aSMA expression. BAY 60-4552 and vardenafil have synergistic effects on relaxation of HCC of PDE5-i nonresponders. The main limitation is the small amount of control tissue precluding functional testing on these samples. Despite downregulation of the NO

Safety and effectiveness of tadalafil in pediatric patients with pulmonary arterial hypertension: a sub-group analysis based on Japan post-marketing surveillance.

PubMed

Yamazaki, Hiroyoshi; Kobayashi, Noriko; Taketsuna, Masanori; Tajima, Koyuki; Suzuki, Nahoko; Murakami, Masahiro

2017-12-01

To evaluate the long-term safety and effectiveness of tadalafil in pediatric patients with pulmonary arterial hypertension (PAH) in real-world clinical practice. This is an observational surveillance of PAH patients receiving tadalafil in the contracted sites. A sub-group analysis was performed of 391 pediatric PAH patients (<18 years) who were included from 1,704 total patients in this surveillance. Safety was assessed from the frequency of adverse drug reactions (ADRs), discontinuations due to adverse events (AEs), and serious adverse drug reactions (SADRs). Effectiveness measurements included change in World Health Organization (WHO) functional classification of PAH, cardiac catheterization (pulmonary arterial pressure: PAP), and echocardiography (tricuspid regurgitation pressure gradient: TRPG). Survival rate was also measured. The mean patient age was 5.7 ± 5.34 years. Associated PAH (APAH) and idiopathic PAH (IPAH) accounted for 76.0% and 17.6%, respectively, of the PAH patients. Patients were followed for up to 2 years. Among 391 patients analyzed for safety, the overall incidence rate of ADRs was 16.6%. The common ADRs (≥ 1%) were headache (2.8%), hepatic function abnormal, platelet count decreased (1.3% each), and epistaxis, (1.0%). Eleven patients (2.8%) reported 16 SADRs. Three patients died secondary to SADRs. For the effectiveness analysis, the incidence of WHO functional class improvement at 3 months, 1 year, and 2 years after the initiation of tadalafil and last observation in pediatric patients were 16.5%, 19.7%, and 16.3%, respectively. Both PAP and TRPG showed a statistically significant reduction at last observation. This manuscript reveals the use of tadalafil in the real-world pediatric population with an acceptable safety profile in Japan.

Developmental toxicity of orally administered sildenafil citrate (Viagra) in SWR/J mice

PubMed Central

Abou-Tarboush, Faisal Mohamed; Abdel-Samad, Mohamed Fathy; Al-Meteri, Mokhlid Hamed

2010-01-01

Normal adult inbred SWR/J mice were used to investigate the teratogenic and other possible toxic effects of various dose levels of sildenafil citrate (Viagra) on fetuses. Multiple dose levels of 6.5, 13.0, 19.5, 26.0, 32.5 or 40.0 mg of sildenafil citrate/kg body weight (which correspond to the multiples of 1, 2, 3, 4, 5 or 6 of human 50 mg Viagra, respectively) were orally administered into pregnant mice on days 7–9, 10–12 or 13–15 of gestation. On day 17 of pregnancy, all fetuses were removed and examined for toxic phenomena (embryo-fetal toxicity) and for external, internal and skeletal malformations. A total of 285 pregnant mice were used in the present study. None of the dams treated with sildenafil citrate at any of the oral dose levels used in the present study died during the experimental period and all dams treated with the drug failed to reveal overt signs of maternal toxicity. Moreover, the results of the present study clearly demonstrate that none of the multiple oral dose levels of the drug at any time interval used has induced any external, internal or skeletal malformations in the fetuses obtained from treated females. However, the dose level of 40 mg/kg body weight of sildenafil citrate has a growth suppressing effect on alive fetuses when it was administered at all the time intervals used in the present study. Furthermore, the dose levels 26.0, 32.5 and 40 mg/kg of the drug have embryo-fetal toxicity when the drug is applied on days 13–15 of gestation. The possible mechanisms involved in the embryo-fetal toxicity and fetal growth suppressing effects of sildenafil citrate were discussed. The results of this study have important implications for the widespread use of this drug. PMID:23961116

Developmental toxicity of orally administered sildenafil citrate (Viagra) in SWR/J mice.

PubMed

Abou-Tarboush, Faisal Mohamed; Abdel-Samad, Mohamed Fathy; Al-Meteri, Mokhlid Hamed

2011-04-01

Normal adult inbred SWR/J mice were used to investigate the teratogenic and other possible toxic effects of various dose levels of sildenafil citrate (Viagra) on fetuses. Multiple dose levels of 6.5, 13.0, 19.5, 26.0, 32.5 or 40.0 mg of sildenafil citrate/kg body weight (which correspond to the multiples of 1, 2, 3, 4, 5 or 6 of human 50 mg Viagra, respectively) were orally administered into pregnant mice on days 7-9, 10-12 or 13-15 of gestation. On day 17 of pregnancy, all fetuses were removed and examined for toxic phenomena (embryo-fetal toxicity) and for external, internal and skeletal malformations. A total of 285 pregnant mice were used in the present study. None of the dams treated with sildenafil citrate at any of the oral dose levels used in the present study died during the experimental period and all dams treated with the drug failed to reveal overt signs of maternal toxicity. Moreover, the results of the present study clearly demonstrate that none of the multiple oral dose levels of the drug at any time interval used has induced any external, internal or skeletal malformations in the fetuses obtained from treated females. However, the dose level of 40 mg/kg body weight of sildenafil citrate has a growth suppressing effect on alive fetuses when it was administered at all the time intervals used in the present study. Furthermore, the dose levels 26.0, 32.5 and 40 mg/kg of the drug have embryo-fetal toxicity when the drug is applied on days 13-15 of gestation. The possible mechanisms involved in the embryo-fetal toxicity and fetal growth suppressing effects of sildenafil citrate were discussed. The results of this study have important implications for the widespread use of this drug.

Physicochemical and Microbiological Stability of the Extemporaneous Sildenafil Citrate Oral Suspension

PubMed Central

Sae Yoon, Attawadee; Sawatdee, Somchai; Woradechakul, Chuthamas; Sae Chee, Kridsada; Atipairin, Apichart

2015-01-01

Sildenafil is a potent and selective phosphodiesterase-5 inhibitor that is effectively used in the treatment of pulmonary arterial hypertension. In several countries, hospital pharmacists prepare the drug in an extemporaneous liquid preparation as there are no liquid formulations available for pediatric and adult uses. The purpose of this study was to evaluate the stability of an extemporaneous sildenafil citrate oral suspension for 90 days, according to the ASEAN guideline on stability studies of drug products. The results showed that the preparation was a white suspension with a sweet taste. It was a viscous and weakly acidic mixture with pseudoplastic behavior. The drug content was in the range between 99.23% and 102.23%, and the microbial examination met the general requirements throughout the study period. Therefore, the extemporaneously compounded sildenafil suspensions were physically, chemically, and microbiologically stable for at least 90 days when stored at 30° and 40°C. Furthermore, the in-use stability study showed that the preparations had acceptable attributes at least 14 days after the first-time use. This might provide an alternative option when the commercial suspension is unavailable. PMID:26839846

Physicochemical and Microbiological Stability of the Extemporaneous Sildenafil Citrate Oral Suspension.

PubMed

Sae Yoon, Attawadee; Sawatdee, Somchai; Woradechakul, Chuthamas; Sae Chee, Kridsada; Atipairin, Apichart

2015-01-01

Sildenafil is a potent and selective phosphodiesterase-5 inhibitor that is effectively used in the treatment of pulmonary arterial hypertension. In several countries, hospital pharmacists prepare the drug in an extemporaneous liquid preparation as there are no liquid formulations available for pediatric and adult uses. The purpose of this study was to evaluate the stability of an extemporaneous sildenafil citrate oral suspension for 90 days, according to the ASEAN guideline on stability studies of drug products. The results showed that the preparation was a white suspension with a sweet taste. It was a viscous and weakly acidic mixture with pseudoplastic behavior. The drug content was in the range between 99.23% and 102.23%, and the microbial examination met the general requirements throughout the study period. Therefore, the extemporaneously compounded sildenafil suspensions were physically, chemically, and microbiologically stable for at least 90 days when stored at 30° and 40°C. Furthermore, the in-use stability study showed that the preparations had acceptable attributes at least 14 days after the first-time use. This might provide an alternative option when the commercial suspension is unavailable.

Bioequivalence study of a new sildenafil 100 mg orodispersible film compared to the conventional film-coated 100 mg tablet administered to healthy male volunteers

PubMed Central

Radicioni, Milko; Castiglioni, Chiara; Giori, Andrea; Cupone, Irma; Frangione, Valeria; Rovati, Stefano

2017-01-01

A new orodispersible film formulation of the phosphodiesterase type 5 inhibitor, sildenafil, has been developed to examine the advantages of an orally disintegrating film formulation and provide an alternative to the current marketed products for the treatment of erectile dysfunction. The pharmacokinetics of the sildenafil 100 mg orodispersible film (IBSA) was compared to that of the conventional marketed 100 mg film-coated tablet (Viagra®) after single-dose administration to 53 healthy male volunteers (aged 18–51 years) in a randomized, open, two-way crossover bioequivalence study. Each subject received a single oral dose of 100 mg of sildenafil as test or reference formulation administered under fasting conditions at each of the two study periods according to a randomized crossover design. There was a washout interval of ≥7 days between the two administrations of the investigational medicinal products. Blood samples for pharmacokinetic analysis were collected up to 24 h post-dosing. The primary objective was to compare the rate (peak plasma concentration; Cmax) and extent (area under the curve [AUC] from administration to last observed concentration time; AUC0–t) of sildenafil absorption after single-dose administration of test and reference. Secondary endpoints were observed to describe the plasma pharmacokinetic profiles of sildenafil and its metabolite N-desmethyl-sildenafil relative bioavailability and safety profile after single-dose administration. The mean sildenafil and N-desmethyl-sildenafil plasma concentration–time profiles up to 24 h after single-dose administration of sildenafil 100 mg orodispersible film and film-coated tablet were nearly superimposable. The bioequivalence test was fully satisfied for sildenafil and N-desmethyl-sildenafil in terms of rate and extent of bioavailability. Adverse events occurred at similar rates for the two formulations and were of mild-to-moderate severity. The results suggest that the new orodispersible film

Bioequivalence study of a new sildenafil 100 mg orodispersible film compared to the conventional film-coated 100 mg tablet administered to healthy male volunteers.

PubMed

Radicioni, Milko; Castiglioni, Chiara; Giori, Andrea; Cupone, Irma; Frangione, Valeria; Rovati, Stefano

2017-01-01

A new orodispersible film formulation of the phosphodiesterase type 5 inhibitor, sildenafil, has been developed to examine the advantages of an orally disintegrating film formulation and provide an alternative to the current marketed products for the treatment of erectile dysfunction. The pharmacokinetics of the sildenafil 100 mg orodispersible film (IBSA) was compared to that of the conventional marketed 100 mg film-coated tablet (Viagra ® ) after single-dose administration to 53 healthy male volunteers (aged 18-51 years) in a randomized, open, two-way crossover bioequivalence study. Each subject received a single oral dose of 100 mg of sildenafil as test or reference formulation administered under fasting conditions at each of the two study periods according to a randomized crossover design. There was a washout interval of ≥7 days between the two administrations of the investigational medicinal products. Blood samples for pharmacokinetic analysis were collected up to 24 h post-dosing. The primary objective was to compare the rate (peak plasma concentration; C max ) and extent (area under the curve [AUC] from administration to last observed concentration time; AUC 0-t ) of sildenafil absorption after single-dose administration of test and reference. Secondary endpoints were observed to describe the plasma pharmacokinetic profiles of sildenafil and its metabolite N-desmethyl-sildenafil relative bioavailability and safety profile after single-dose administration. The mean sildenafil and N-desmethyl-sildenafil plasma concentration-time profiles up to 24 h after single-dose administration of sildenafil 100 mg orodispersible film and film-coated tablet were nearly superimposable. The bioequivalence test was fully satisfied for sildenafil and N-desmethyl-sildenafil in terms of rate and extent of bioavailability. Adverse events occurred at similar rates for the two formulations and were of mild-to-moderate severity. The results suggest that the new orodispersible film

Effect of combined locally delivered growth factors and systemic sildenafil citrate on microrecanalization in biodegradable conduit for vas deferens reconstruction.

PubMed

Rosevear, Henry M; Krishnamachari, Yogita; Ariza, Carlos A; Mallapragada, Surya K; Salem, Aliasger K; Griffith, Thomas S; De Young, Barry R; Wald, Moshe

2012-04-01

To investigate the effect of the combination of locally delivered growth factors and oral sildenafil citrate on cross-conduit microrecanalization. A total of 42 rats were divided into 7 groups. Of the 42 rats, 6 underwent bilateral vasectomy and bilateral end-to-end vasovasostomy and 12 underwent bilateral vasectomy. Of the latter 12, 6 received sildenafil citrate orally (10 mg/kg/d) for 24 weeks and 6 received placebo. A total of 24 rats underwent bilateral vasectomy and bilateral reconstruction with implantation of a 5-mm biodegradable conduit that bridged the 2 vasal ends. Of the 24 rats with conduits, 12 also had 250 pg of transforming growth factor-β and 12.5 pg of platelet-derived growth factor-β sustained release nanoparticles placed in immediate proximity to the conduit. The remaining 12 rats with conduits (6 without growth factors and 6 with growth factors) also received sildenafil citrate orally (10 mg/kg/d) for 24 weeks; the others received placebo. The reconstructed segments were harvested for histologic examination at 24 weeks. Five of 6 primary vasovasostomy and no vasectomy-only rats sired litters. Significantly more microcanals per conduit were observed in rats receiving sildenafil citrate: without growth factors, 3.9 vs. 0 canals/conduit (P < 0.001); with growth factors, 5.5 vs. 0.25 canals/conduit (P < 0.001). The rats receiving sildenafil citrate with growth factors showed a trend toward more microcanals per conduit than the rats receiving sildenafil citrate without growth factors (5.5 vs 3.9; P = .10). Rats receiving growth factors but no sildenafil citrate did not produce more canals than the rats receiving neither growth factor nor sildenafil citrate (0.25 vs 0; P = NS). Orally administered sildenafil citrate enhances formation of microcanalization after postvasectomy reconstruction using a biodegradable conduit in a rat model. Locally delivered growth factors appear to increase the number of microcanals. Copyright © 2012 Elsevier Inc. All

Treatment satisfaction with tadalafil or tamsulosin vs placebo in men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH): results from a randomised, placebo-controlled study.

PubMed

Oelke, Matthias; Giuliano, François; Baygani, Simin K; Melby, Thomas; Sontag, Angelina

2014-10-01

To assess treatment satisfaction with tadalafil or tamsulosin vs placebo in a 12-week, randomised, double-blind study of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH). After a 4-week placebo lead-in period, men aged ≥45 years with an International Prostate Symptom Score (IPSS) of ≥13 and a maximum urinary flow rate of ≥4 to ≤15 mL/s received placebo (172 men), tadalafil 5 mg (171), or tamsulosin 0.4 mg (168) once daily for 12 weeks. Treatment Satisfaction Scale-BPH (TSS-BPH) responses were assessed based on median treatment differences using the van Elteren test. Overall treatment satisfaction was greater for tadalafil vs placebo (P = 0.005), based on greater satisfaction with efficacy (P = 0.003); neither overall treatment satisfaction nor satisfaction with efficacy was greater for tamsulosin vs placebo (P ≥ 0.409). For individual questions, 66.5% of men rated tadalafil treatment as 'effective/very effective' (Question 1, Q1) vs placebo (P = 0.011), 72.6% would 'definitely/probably recommend their treatment' (Q3; P = 0.043), 71.8% were generally 'very satisfied/satisfied with their medication' (Q8; P < 0.003), and 65.0% would 'definitely/probably continue therapy' (Q10; P = 0.035). With tamsulosin, differences vs placebo were not statistically significant. Subgroup analyses of overall TSS-BPH by baseline age (≤65/>65 years), history of erectile dysfunction (yes/no), LUTS/BPH severity (IPSStadalafil vs placebo, with only borderline difference for men without prior therapy. Treatment satisfaction was greater with tadalafil vs placebo, with no significant difference between tamsulosin and placebo. © 2014 The Authors. BJU International

Sildenafil citrate improves the delivery and anticancer activity of doxorubicin formulations in a mouse model of breast cancer.

PubMed

Greish, Khaled; Fateel, Maryam; Abdelghany, Sara; Rachel, Nanitha; Alimoradi, Houman; Bakhiet, Moiz; Alsaie, Ahmed

2017-11-21

Sildenafil is an approved drug for the treatment of erectile dysfunction. The drug exerts its action through the relaxation of smooth muscles and the modulation of vascular endothelial permeability. In this work, we tested whether the aforementioned effects of sildenafil on tumour vasculatures could result in an improvement of anticancer drug concentration in tumour tissues and hence improves its anticancer effect. Sildenafil when added to doxorubicin showed synergistic anticancer activity against 4T1 breast cancer cells in vitro. Adding 1, 30 and 100 μM of Viagra to 1 μM of doxorubicin resulted in 1.8-fold, 6.2-fold and 21-fold statistically significant increases in its cytotoxic effect, respectively. As a result, 4T1 tumour-bearing mice showed up to 2.7-fold increase in drug concentrations of the fluorescent Dye DiI and doxorubicin in tumour tissues, as well as their nanoformulations. Animals treated with the combinations of both Sildenafil citrate and doxorubicin showed a statistically significant 4.7-fold reduction in tumour size compared to doxorubicin alone. This work highlights the effect of Sildenafil on tumour vasculatures and provides a rational for further testing the combination on breast cancer patients.

A randomized, double-blind, placebo-controlled, cross-over study to assess the efficacy of tadalafil (Cialis[reg]) in the treatment of erectile dysfunction following three-dimensional conformal external-beam radiotherapy for prostatic carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Incrocci, Luca; Slagter, Cleo; Slob, A. Koos

2006-10-01

Purpose: Erectile dysfunction after three-dimensional conformal external-beam radiotherapy (3DCRT) for prostatic carcinoma is reported in as many as 64% of those patients. The purpose of this study was to determine the efficacy of the oral drug tadalafil (Cialis (registered) ) in patients with erectile dysfunction after radiotherapy for prostatic carcinoma. Methods and Materials: Patients (N = 358) who completed radiotherapy at least 12 months before the study were approached by mail. All patients had been treated by 3DCRT; 60 patients were included and entered a double-blind, placebo-controlled, cross-over study lasting 12 weeks. They received 20 mg of tadalafil or placebomore » for 6 weeks. Drug or placebo was taken on demand at patient's discretion, with no restrictions regarding the consumption of alcohol or food, at least once a week and no more than once daily. At 6 weeks patients crossed over to the alternative treatment. Data were collected using the Sexual Encounter Profile (SEP) and the International Index of Erectile Function (IIEF) questionnaires. Side effects were also recorded. Results: Mean age at study entry was 69 years. All patients completed the study. For almost all questions of the IIEF questionnaire there was a significant increase in mean scores from baseline with tadalafil, but not with placebo. Sixty-seven percent of the patients reported an improvement of erectile function with tadalafil (placebo: 20%), and 48% reported successful intercourse with tadalafil (placebo: 9%) (p < 0.0001). Side effects were mild or moderate. Conclusions: Tadalafil is an effective treatment for erectile dysfunction after 3DCRT for prostatic carcinoma with successful intercourse reported in almost 50% of the patients, and it is well tolerated.« less

Evaluation of Pharmacokinetic and Pharmacodynamic Drug-Drug Interaction of Sacubitril/Valsartan (LCZ696) and Sildenafil in Patients With Mild-to-Moderate Hypertension.

PubMed

Hsiao, H-L; Langenickel, T H; Petruck, J; Kode, K; Ayalasomayajula, S; Schuehly, U; Greeley, M; Pal, P; Zhou, W; Prescott, M F; Sunkara, G; Rajman, I

2018-03-01

Sacubitril/valsartan (LCZ696) is indicated for the treatment of patients with heart failure and reduced ejection fraction (HFrEF). Since patients with HFrEF may receive sacubitril/valsartan and sildenafil, both increasing cyclic guanosine monophosphate, the present study evaluated the pharmacokinetic and pharmacodynamic drug interaction potential between sacubitril/valsartan and sildenafil. In this open-label, three-period, single sequence study, patients with mild-to-moderate hypertension (153.8 ± 8.2 mmHg mean systolic blood pressure (SBP)) received a single dose of sildenafil 50 mg, sacubitril/valsartan 400 mg once daily for 5 days, and sacubitril/valsartan and sildenafil coadministration. When coadministered with sildenafil, the AUC and C max of valsartan decreased by 29% and 39%, respectively. Coadministration of sacubitril/valsartan and sildenafil resulted in a greater decrease in BP (-5/-4/-4 mmHg mean ambulatory SBP/DBP/MAP (mean arterial pressure)) than with sacubitril/valsartan alone. Both treatments were generally safe and well tolerated in this study; however, the additional BP reduction suggests that sildenafil should be administered cautiously in patients receiving sacubitril/valsartan. Unique identifier: NCT01601470. © 2017 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

The protective effects of sildenafil in acute lung injury in a rat model of severe scald burn: A biochemical and histopathological study.

PubMed

Gokakin, Ali Kagan; Deveci, Koksal; Kurt, Atilla; Karakus, Boran Cihat; Duger, Cevdet; Tuzcu, Mehmet; Topcu, Omer

2013-09-01

Severe burn induces biochemical mediators such as reactive oxygen species that leads to lipid peroxidation which may have a key role in formation of acute lung injury (ALI). Sildenafil is a selective and potent inhibitor of cyclic guanosine monophosphate specific phosphodiesterase-5. Sildenafil preserves alveolar growth, angiogenesis, reduces inflammation and airway reactivity. The purpose of the present study was to evaluate the effects of different dosages of sildenafil in ALI due to severe scald burn in rats. Twenty-four rats were subjected to 30% total body surface area severe scald injury and were randomly divided into three equal groups as follow: control, 10 and 20mg/kg sildenafil groups. Levels of malondialdehyde (MDA), activities of glutathione peroxidase (Gpx), catalase (Cat), total oxidative stress (TOS), and total antioxidative capacity (TAC) were measured in both tissues and serums. Oxidative stress index (OSI) was calculated. A semi-quantitative scoring system was used for the evaluation of histopatological findings. Sildenafil increased Gpx, Cat, TAC and decreased MDA, TOS and OSI. Sildenafil decreased inflammation scores in lungs. Our results reveal that sildenafil is protective against scald burn related ALI by decreasing oxidative stress and inflammation and the dosage of 10mg/kg could be apparently better than 20mg/kg. Copyright © 2013 Elsevier Ltd and ISBI. All rights reserved.

The effects of sildenafil in liver and kidney injury in a rat model of severe scald burn: a biochemical and histopathological study.

PubMed

Gökakın, Ali Kağan; Atabey, Mustafa; Deveci, Koksal; Sancakdar, Enver; Tuzcu, Mehmet; Duger, Cevdet; Topcu, Omer

2014-09-01

Severe burn induces systemic inflammation and reactive oxygen species leading to lipid peroxidation which may play role in remote organs injury. Sildenafil is a selective and potent inhibitor of cyclic guanosine monophosphate specific phosphodiesterase-5. Sildenafil reduces oxidative stress and inflammation in distant organs. The aim of the present study was to evaluate the effects of different dosages of sildenafil in remote organs injury. A total of thirty-two rats were randomly divided into four equal groups. The groups were designated as follows: Sham, Control, 10, and T20 mg/kg sildenafil treatment groups. Levels of malondialdehyde (MDA), vascular endothelial growth factor (VEGF), VEGF receptor (Flt-1), activities of glutathione peroxidase (Gpx), levels of total antioxidative capacity (TAC), and total oxidant status (TOS) were measured in both tissues and serum, and a semi-quantitative scoring system was used for the evaluation of histopathological findings. Sildenafil increased levels of Gpx, and Flt-1, and decreased MDA and VEGF levels in tissues. Sildenafil also increased serum levels of TAC and Flt-1 and decreased TOS, OSI, and VEGF. Sildenafil decreased inflammation scores in remote organs in histopathological evaluation. It has protective effects in severe burn-related remote organ injuries by decreasing oxidative stress and inflammation.

Treatment of Palmar Plantar Erythrodysesthesia (PPE) with Topical Sildenafil: A Pilot Study

PubMed Central

Meadows, Kellen L.; Rushing, Christel; Honeycutt, Wanda; Latta, Kenneth; Howard, Leigh; Arrowood, Christy A.; Niedzwiecki, Donna; Hurwitz, Herbert I.

2016-01-01

Purpose Palmar-plantar erythrodysethesia (PPE) is a common chemotherapy and anti-VEGF multi-kinase inhibitor class-related toxicity that often results in debilitating skin changes and often limits the use of active anti-cancer regimens. Mechanistic and anecdotal clinical evidence suggested that topical application of sildenafil cream may help reduce the severity of PPE. Therefore, we conducted a randomized, double-blind, placebo-controlled pilot study to evaluate the feasibility, safety and efficacy of topical sildenafil cream for the treatment of PPE. Methods Eligible subjects were required to have grade 1–3 PPE associated with either capecitabine or sunitinib. Subjects were randomized to receive 1% topical sildenafil cream to the left extremities or right extremities and placebo cream on the opposite extremity. 0.5 mL of cream was applied to each affected hand/foot two times per day. The primary endpoint was improvement in PPE grading at any point on study. Clinical assessments were evaluated by NCI-CTC 4.0 grading and patient self-reported pain. Results Ten subjects were enrolled; 9 were evaluable for safety and efficacy. Five of nine subjects reported some improvement in foot pain and 3 of 8 subjects for hand pain improvement. One of these subjects noted specific improvement in tactile function. No treatment-related toxicities were observed. Conclusions In this limited, single center study, topical cream containing 1% sildenafil is feasible to administer, is well-tolerated, and may mitigate PPE-related symptoms due to anti-cancer therapeutic agents. Further validation is necessary. PMID:25341548

Sildenafil citrate in the treatment of pain in primary dysmenorrhea: a randomized controlled trial†

PubMed Central

Dmitrovic, R.; Kunselman, A.R.; Legro, R. S.

2013-01-01

STUDY QUESTION Is a vaginal preparation of sildenafil citrate capable of alleviating acute menstrual pain in patients with primary dysmenorrhea (PD)? SUMMARY ANSWER A vaginal preparation of sildenafil citrate is capable of alleviating acute menstrual pain in patients with PD with no observed adverse effects. WHAT IS KNOWN ALREADY Oral preparations of nitric oxide (NO) donor drugs augment relaxant effects of NO on myometrial cells, reverse the vasoconstriction caused by prostaglandins and successfully alleviate pain, but the incidence of side effects is too high for routine clinical use. Sildenafil citrate inhibits type 5-specific phosphodiesterase (PDE5), thus preventing the degradation of cyclic guanosine monophosphate (cGMP) in the muscle and augmenting the vasodilatory effects of NO. Therefore, by inhibiting PDE5, the tissue remains relaxed and more blood can circulate through. It has been used previously in a vaginal form with no observed side effects, and it enhances endometrial blood flow. STUDY DESIGN, SIZE, DURATION A double-blind, randomized, controlled trial comparing vaginal preparation of sildenafil citrate (100 mg single dose) to a placebo in 62 PD patients at the time of painful menstruation was conducted. The primary outcome was total pain relief over 4 consecutive hours (TOPAR4) comparing sildenafil citrate to placebo, where higher TOPAR4 scores represent better pain relief. Secondary outcomes were pain relief as measured by the visual analog scale (VAS) and uterine artery pulsatility index (PI). Subjects were recruited from December 2007 to January 2011. The trial was stopped due to closeout of the funding for the study. PARTICIPANTS, SETTINGS, METHODS Participants were women in good health, were aged 18–35 years and suffered from moderate to severe PD. They were randomized to either vaginal placebo or 100 mg vaginal sildenafil citrate in a 1:1 ratio using random permuted blocks having a block size of 4. At baseline and 1, 2, 3, and 4 h post

Sildenafil citrate in the treatment of pain in primary dysmenorrhea: a randomized controlled trial.

PubMed

Dmitrovic, R; Kunselman, A R; Legro, R S

2013-11-01

Is a vaginal preparation of sildenafil citrate capable of alleviating acute menstrual pain in patients with primary dysmenorrhea (PD)? A vaginal preparation of sildenafil citrate is capable of alleviating acute menstrual pain in patients with PD with no observed adverse effects. Oral preparations of nitric oxide (NO) donor drugs augment relaxant effects of NO on myometrial cells, reverse the vasoconstriction caused by prostaglandins and successfully alleviate pain, but the incidence of side effects is too high for routine clinical use. Sildenafil citrate inhibits type 5-specific phosphodiesterase (PDE5), thus preventing the degradation of cyclic guanosine monophosphate (cGMP) in the muscle and augmenting the vasodilatory effects of NO. Therefore, by inhibiting PDE5, the tissue remains relaxed and more blood can circulate through. It has been used previously in a vaginal form with no observed side effects, and it enhances endometrial blood flow. A double-blind, randomized, controlled trial comparing vaginal preparation of sildenafil citrate (100 mg single dose) to a placebo in 62 PD patients at the time of painful menstruation was conducted. The primary outcome was total pain relief over 4 consecutive hours (TOPAR4) comparing sildenafil citrate to placebo, where higher TOPAR4 scores represent better pain relief. Secondary outcomes were pain relief as measured by the visual analog scale (VAS) and uterine artery pulsatility index (PI). Subjects were recruited from December 2007 to January 2011. The trial was stopped due to closeout of the funding for the study. Participants were women in good health, were aged 18-35 years and suffered from moderate to severe PD. They were randomized to either vaginal placebo or 100 mg vaginal sildenafil citrate in a 1:1 ratio using random permuted blocks having a block size of 4. At baseline and 1, 2, 3, and 4 h post-treatment, patients were asked to provide assessment of their degree of pain using two scales: (i) pain on the 5-level

Erection capability is potentiated by long-term sildenafil treatment: role of blood flow-induced endothelial nitric-oxide synthase phosphorylation.

PubMed

Musicki, Biljana; Champion, Hunter C; Becker, Robyn E; Liu, Tongyun; Kramer, Melissa F; Burnett, Arthur L

2005-07-01

Despite demonstrated clinical efficacy of sildenafil for the temporary treatment of erectile dysfunction, the possibility that sildenafil used long-term durably augments erectile ability remains unclear. We investigated whether continuous long-term administration of sildenafil at clinically relevant levels to aged rats "primes" the penis for improved erectile ability and involves nitric oxide (NO) or RhoA/Rho-kinase signaling pathways. In aged, but not young rats, sildenafil prolonged erection and increased the protein expressions of phosphorylated endothelial NO synthase (eNOS) at serine-1177 and phosphorylated Akt at serine-473 in penes. Only in the young rat penis, protein expressions of phosphodiesterase-5 and phosphomyosin phosphatase target subunit 1, a marker of Rho-kinase activity, were increased by sildenafil. Sildenafil inhibited phosphodiesterase-5 activity in penes of young and aged rats coincident with assayed free plasma levels of the drug equivalent to clinically therapeutic measurements. We conclude that erectile ability can be enhanced under preconditions of erectile impairment by long-term inhibition of phosphodiesterase-5 and that the effect is mediated by Akt-dependent eNOS phosphorylation. The lack of erectile ability enhancement in young rats by long-term phosphodiesterase-5 inhibition may relate to restrained NO signaling by phosphodiesterase-5 up-regulation, lack of incremental Akt and eNOS phosphorylation, and heightened Rho-kinase signaling in the penis.

Protective effect of co-administration of curcumin and sildenafil in alcohol induced neuropathy in rats.

PubMed

Kaur, Maninder; Singh, Amarjeet; Kumar, Bimlesh; Singh, Sachin Kumar; Bhatia, Amit; Gulati, Monica; Prakash, T; Bawa, Palak; Malik, Adil Hussain

2017-06-15

Neuropathic pain associated with chronic alcohol consumption is a medico-socioeconomical problem that affects both central and peripheral nervous system and has no satisfactory treatment till date. The present study was designed to investigate the protective effect of co-administration of curcumin and sildenafil on alcohol induced neuropathic pain in rats. In order to carry out this, ethanol (35% v/v, 10g/kg, p.o.) was administered for 10 weeks to induce neuropathic pain. Curcumin (30 and 60mg/kg, i.p.) and sildenafil (5 and 10mg/kg, i.p.) were given alone and in combination at their lower doses (30mg/kg curcumin and 5mg/kg, sildenafil, i.p.) to investigate the changes in thermal and mechanical hyperalgesia, allodynia and histopathological parameters. Biochemical estimations of thiobarbituric acid reactive species, glutathione and protein was also carried out to evaluate oxidative stress. The results revealed that chronic alcohol consumption for 10 weeks caused significant thermal and mechanical hyperalgesia, allodynia and increased oxidative stress. Individual administration of both the drugs at their low as well as high doses were able to improve the symptoms of alcohol induced neuropathic pain. Whereas co-administration of curcumin and sildenafil at their lower doses itself were found to significantly improve nerve functions, biochemical and histopathological parameters as compared to their individual administration. It is therefore proposed that co-administration of curcumin and sildenafil may bring new dimension towards attenuation of alcohol induced neuropathic pain affecting central as well as peripheral nervous system. Copyright © 2017 Elsevier B.V. All rights reserved.

Neurophysiological role of sildenafil citrate (Viagra) on seminal parameters in diabetic males with and without neuropathy.

PubMed

Ali, Syed Tabrez; Rakkah, Nabeeh I

2007-01-01

Sildenafil citrate is a specific inhibitor of phosphodiesterase (PDE) type-5 and represents a powerful therapy for male erectile and fertility dysfunctions of different etiologies. Present study demonstrates whether sildenafil administration modifies seminal parameters in diabetic neuropathic patients. In this investigation 50 insulin dependent (IDDM) and 50 non insulin dependent (NIDDM) diabetic male patients with and without an objective evidence of neuropathy and 50 age matched non diabetic male controls were selected. Every male had age between 20 to 65 years with duration of diabetes distributed over 1 to 20 years. Treatment with 100 mg of oral sildenafil citrate on seminal parameters was evaluated by semen analysis in these patients. In both IDDM and NIDDM diabetic neuropathic patients, chronic sildenafil treatment exhibited a significant decrease in total sperm output and sperm concentration (p<0.001). On the other hand, sperm motility and semen volume were found to be increased by about 40% and 48% respectively in these patients, where as sperm morphology and quality of sperm motility remained unaffected. However both types of non neuropathic diabetics showed a non significant difference in all the above mentioned parameters when compared with the untreated groups and their respective control subjects. A comparison between IDDM and NIDDM neuropathic and non neuropathic diabetic groups further indicated a non significant difference in all the parameters of semen analysis. These findings suggest a chronic neuro physiological effect of sildenafil treatment on male fertility profile exclusively in diabetic neuropathic condition with an improvement in testicular function which was probably arrested due to some kind of testicular hyperplasia resulted by testicular necrosis and promoted spermatogenesis. Sildenafil seems to be associated with an improvement in the entire smooth musculature of reproductive tract and testicular morphology which was altered due to

Development of a Video-Microscopic Tool To Evaluate the Precipitation Kinetics of Poorly Water Soluble Drugs: A Case Study with Tadalafil and HPMC.

PubMed

Christfort, Juliane Fjelrad; Plum, Jakob; Madsen, Cecilie Maria; Nielsen, Line Hagner; Sandau, Martin; Andersen, Klaus; Müllertz, Anette; Rades, Thomas

2017-12-04

Many drug candidates today have a low aqueous solubility and, hence, may show a low oral bioavailability, presenting a major formulation and drug delivery challenge. One way to increase the bioavailability of these drugs is to use a supersaturating drug delivery strategy. The aim of this study was to develop a video-microscopic method, to evaluate the effect of a precipitation inhibitor on supersaturated solutions of the poorly soluble drug tadalafil, using a novel video-microscopic small scale setup. Based on preliminary studies, a degree of supersaturation of 29 was chosen for the supersaturation studies with tadalafil in FaSSIF. Different amounts of hydroxypropyl methyl cellulose (HPMC) were predissolved in FaSSIF to give four different concentrations, and the supersaturated system was then created using a solvent shift method. Precipitation of tadalafil from the supersaturated solutions was monitored by video-microscopy as a function of time. Single-particle analysis was possible using commercially available software; however, to investigate the entire population of precipitating particles (i.e., their number and area covered in the field of view), an image analysis algorithm was developed (multiparticle analysis). The induction time for precipitation of tadalafil in FaSSIF was significantly prolonged by adding 0.01% (w/v) HPMC to FaSSIF, and the maximum inhibition was reached at 0.1% (w/v) HPMC, after which additional HPMC did not further increase the induction time. The single-particle and multiparticle analyses yielded the same ranking of the HPMC concentrations, regarding the inhibitory effect on precipitation. The developed small scale method to assess the effect of precipitation inhibitors can speed up the process of choosing the right precipitation inhibitor and the concentration to be used.

Effects of sildenafil citrate (viagra) on cardiac repolarization and on autonomic control in subjects with chronic heart failure.

PubMed

Piccirillo, Gianfranco; Nocco, Marialuce; Lionetti, Marco; Moisè, Antonio; Naso, Camilla; Marigliano, Vincenzo; Cacciafesta, Mauro

2002-04-01

Cases of sudden death associated with sildenafil citrate use have been reported in men with coronary artery disease. The aim of this study was to investigate the drug's effect on cardiac repolarization and sinus autonomic and vascular control in men with mild chronic heart failure (CHF; New York Heart Association classification II). Changes in these variables could predispose patients to malignant ventricular arrhythmias. We measured QT dispersion, the QT-RR slope, and the index of QT variability (QTVI) and analyzed spectral power of RR and systolic blood pressure variability in 10 men with dilated cardiomyopathy and in 10 control subjects after administration of a single 50-mg oral dose of sildenafil citrate or placebo at rest (not followed with any attempt at intercourse). In both groups, oral sildenafil citrate decreased the systolic blood pressure (P <.05) and increased the heart rate (P <.05). In subjects with CHF, it also increased the QT-RR (P <.001) and QTVI (from -0.45 +/- 0.07 to -0.27 +/- 0.07; P <.001), but in controls, it increased the QTVI (from -1.20 +/- 0.08 to -0.78 +/-.014; P <.001). In these subjects and controls, oral sildenafil citrate induced a significant reduction in high frequency, expressed in absolute power (subjects with CHF: from 4.04 +/- 0.14 to 3.43 +/- 0.16 natural logarithm ms2; P <.001; controls: from 5.61 +/- 0.44 to 4.98 +/- 0.32 natural logarithm ms2; P <.05) and in normalized units (P <.05). In subjects with CHF but not in controls, it also significantly increased the low frequency to high frequency ratio (from 1.3 +/- 0.12 to 1.89 +/- 0.16; P <.001) and low frequency expressed in normalized units (P <.05). Sildenafil citrate caused no significant changes in the QT interval or dispersion. These findings indicate that, in men with heart failure, sildenafil citrate reduces vagal modulation and increases sympathetic modulation, probably through its reflex vasodilatory action. The autonomic system changes induced with sildenafil

Efficacy of a novel water-soluble curcumin derivative versus sildenafil citrate in mediating erectile function.

PubMed

Zaahkouk, A M S; Abdel Aziz, M T; Rezq, A M; Atta, H M; Fouad, H H; Ahmed, H H; Sabry, D; Yehia, M H

2015-01-01

The present study was conducted to assess the efficacy of a novel curcumin derivative (NCD) versus sildenafil citrate in erectile signaling. The study was conducted on 10 control male rats and 50 diabetic male rats divided into the following groups: diabetic, curcumin, NCD, sildenafil and NCD combined with sildenafil. Cavernous tissue (CC) gene expression levels of heme oxygenase (HO)-1, Nrf2, NF-κβ and p38, enzyme activities of HO and nitric oxide synthase (NOS), cyclic guanosine monophosphate (cGMP) and intracavernosal pressure (ICP) were assessed. Results showed that 12 weeks after induction of diabetes, erectile dysfunction was confirmed by the significant decrease in ICP, a significant decrease in cGMP, NOS, HO enzyme activities, a significant decrease in HO-1 gene and a significant elevation of NF-κβ, p38 genes. Administration of all therapeutic interventions led to a significant elevation in ICP, cGMP levels, a significant increase in HO-1 and NOS enzymes, a significant increase in HO-1 and Nrf2 gene expression, and a significant decrease in NF-κβ, p38 gene expression. NCD or its combination with sildenafil showed significant efficacy and more prolonged duration of action. In conclusion, NCD could enhance erectile function with more efficacy and more prolonged duration of action.

Sildenafil, a selective phosphodiesterase type 5 inhibitor, enhances memory reconsolidation of an inhibitory avoidance task in mice.

PubMed

Boccia, M M; Blake, M G; Krawczyk, M C; Baratti, C M

2011-07-07

Intracellular levels of the second messengers cAMP and cGMP are maintained through a balance between production, carried out by adenyl cyclase (AC) and guanylyl cyclase (GC), and degradation, carried out by phosphodiesterases (PDEs). Recently, PDEs have gained increased attention as potential new targets for cognition enhancement, with particular reference to phosphodiesterase type 5 (PDE5A). It is accepted that once consolidation is completed memory becomes permanent, but it has also been suggested that reactivation (memory retrieval) of the original memory makes it sensitive to the same treatments that affect memory consolidation when given after training. This new period of sensitivity coined the term reconsolidation. Sildenafil (1, 3, and 10mg/kg, ip), a cGMP-PDE5 inhibitor, facilitated retention performance of a one-trial step-through inhibitory avoidance task, when administered to CF-1 male mice immediately after retrieval. The effects of sildenafil (1mg/kg, ip) were time-dependent, long-lasting and inversely correlated with memory age. The administration of sildenafil (1mg/kg, ip) 30 min prior to the 2nd retention test did not affect retention of mice given post-retrieval injections of either vehicle or sildenafil (1mg/kg, ip). Finally, an enhancement of retention was also observed in CF-1 female mice receiving sildenafil (1mg/kg, ip) immediately, but not 180 min after retrieval. In the present paper we reported for the first time that systemic administration of sildenafil after memory reactivation enhances retention performance of the original learning. Our results indirectly point out cGMP, a component of the NO/cGMP/PKG pathway, as a necessary factor for memory reconsolidation. Copyright © 2011 Elsevier B.V. All rights reserved.

[The effect of vaginal sildenafil citrate on uterine blood flow and endometrium in the infertile women].

PubMed

Malinova, M; Abouyta, T; Krasteva, M

2013-01-01

Evaluation of endometrial receptivity remains a challenge in clinical practice. Ultrasound evaluation of endometrial thickness and texture and measurement of uterine artery blood flow has been used for endometrial assessment. To investigate the role of combination of sildenafil citrate and serophene on endometrial thickness, endometrial volume, endometrial FI and VFI on Angiohistogram, RI and PI to a. uterine on the day of hCG, in prediction of IUI outcome in infertile women. Forty two patients were selected randomly who had anovulatory infertility. In Sildenafil citrate plus Serophene group (Group I), patients got 25 mg sildenafil citrate (Silden) vaginally and Serophene 100-150 mg orally, and in Serophene group (Group II), 100-150 mg of Serophene was given orally. Mean endometrial thickness and endometrial volume was 11.8 +/- 2.6 v/s 10.2 +/- 2.8 and 5.2 +/- 1.4 v/s 3.6 +/- 1.8 respectively in group I and in group II (p < 0.05). There was significant decrease in PI and RI to a. uterina in group I. Combination of Sildenafil citrate and Serophene is an effective agent as a first-line of treatment for ovulation induction.

Sildenafil Decreases BACE1 and Cathepsin B Levels and Reduces APP Amyloidogenic Processing in the SAMP8 Mouse.

PubMed

Orejana, Lourdes; Barros-Miñones, Lucía; Jordan, Joaquin; Cedazo-Minguez, Angel; Tordera, Rosa M; Aguirre, Norberto; Puerta, Elena

2015-06-01

The senescence-accelerated mouse-prone 8 (SAMP8), used as a model of aging, displays many established pathological features of Alzheimer's disease. Cognitive impairments and increased levels of hyperphosphorylated tau are found in the hippocampus of SAMP8 mice along with an increased β-secretase activity and amyloid-β (Aβ) depositions that increase in number and extent with age. Based on a previous study from our laboratory showing an amelioration of cognitive impairments and tau pathology by sildenafil, in this study we tested whether this drug could also modulate the amyloid precursor protein amyloidogenic processing in this mouse model. Our results show that the protein levels of the β-secretases β-site amyloid precursor protein cleaving enzyme 1 and cathepsin B are higher in the hippocampus of 9-month-old SAMP8 mice than those of age-matched senescence-resistant-1. Sildenafil (7.5mg/kg for 4 weeks) attenuated learning and memory impairments shown by SAMP8 mice in the passive avoidance test. The increased expression of β-site amyloid precursor protein cleaving enzyme 1 was also reduced by sildenafil, an effect paralleled to decreases in the activities of two β-site amyloid precursor protein cleaving enzyme 1 modulators, calpain and cyclin-dependent kinase 5 protein. Interestingly, sildenafil enhanced both Akt and glycogen synthase kinase-3β (ser9) phosphorylation, which could be mediating the reduction in cathepsin B levels found in the hippocampus of sildenafil-treated SAMP8 mice. Sildenafil-induced reduction in β-site amyloid precursor protein cleaving enzyme 1 and cathepsin B expression in SAMP8 mice was associated with a decrease in hippocampal Aβ42 levels which, in turn, could mediate the parallel decline in glial fibrillary acidic protein expression observed in these animals. These findings highlight the therapeutic potential of sildenafil in Alzheimer's disease pathogenesis. © The Author 2014. Published by Oxford University Press on behalf of

Clinical efficacy and safety of sildenafil citrate (Viagra) in a multi-racial population in Singapore: A retrospective study of 1520 patients.

PubMed

Lim, Peter Huat Chye; Li, Man Kay; Ng, Foo Cheong; Chia, Sing Joo; Consigliere, David; Gooren, Louis; Ng, Kok Kit; Munisamy, Malathy; Perianan, Moorthy

2002-06-01

Sildenafil citrate (Viagra), a selective inhibitor of cGMP-specific phosphodiesterase type-5, has been used as an oral therapeutic drug for erectile dysfunction. The present paper is a clinical study of the success rate and side-effects of the use of sildenafil in a multi-racial population in Singapore. From April 1999 to May 2000, 1520 patients were given sildenafil citrate. Of these, 912 patients (mean age, 54.6 years; age range, 22-99 years) were followed up and evaluated for clinical efficacy and safety of the drug. The mean duration of erectile dysfunction (ED) and follow-up periods were 31.5 and 3.0 months, respectively. Satisfactory erections assessed by single global efficacy question (GEQ) occurred in 83% of patients, major side-effects in the form of flushing (3.48%), headache (1.97%), blurred vision (1.25%), giddiness (1.18%), warmth (1.11%) and others (4.92%) were recorded in 127 patients (13.9%). Racially, Chinese men with ED had higher efficacy (85.7%), compared to Indian men (74.2%) and Malay men (72.8%). With respect to comorbid profiles, an efficacy of 77.8% (n = 271), 83.9% (n = 292), 86.4% (n = 44) and 83.3% (n = 199) was recorded in diabetic, hypertensive, ischemic heart disease patients and in benign prostatic hyperplasia patients, respectively. Patients who smoked (n = 135) and drank alcohol (n = 118) showed an efficacy of 80%. Baseline hormonal profiles of luteinizing hormone, follicle stimulating hormone, testosterone and prolactin did not affect the success rates of sildenafil citrate. Many patients had earlier received other forms of treatment (medicated urethral suppository for erection (MUSE; 84.9%); vacuum devices (86.8%), traditional medicines (100%) and other oral medications (89.2%)), but this did not influence the success rate of sildenafil citrate. But patients previously treated with prostaglandin-E intracavernosal injections were less successful on sildenafil citrate (77.3%). In the total cohort, 50 mg sildenafil citrate was an

Effect of tadalafil 5mg daily treatment on the ejaculatory times, lower urinary tract symptoms and erectile function in patients with erectile dysfunction

PubMed Central

Karabakan, Mehmet; Keskin, Ercument; Akdemir, Serkan; Bozkurt, Aliseydi

2017-01-01

ABSTRACT Objective To investigate the effect of a 5mg daily tadalafil treatment on the ejaculation time, erectile function and lower urinary tract symptoms (LUTS) in patients with erectile dysfunction. Materials and Methods A total of 60 patients diagnosed with erectile dysfunction were retrospectively evaluated using the international index of erectile function questionnaire-5 (IIEF-5), intravaginal ejaculatory latency time (IELT) and international prostate symptoms scores (IPSS). After the patients were treated with 5mg tadalafil once a day for three months, their erection, ejaculation and LUTS were assessed again. The fasting levels of blood glucose, total testosterone, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and total cholesterol were measured. The independent-samples t-test was used to compare the pre- and post-treatment scores of the patients. Results The mean age of the 60 participants was 50.4±7.9 and the mean baseline serum total testosterone, total cholesterol, and fasting blood sugar were 444.6±178.6ng dL-1, 188.7±29.6mg/dL-1,104 (80-360) mg dL-1, respectively. The mean baseline scores were 2.2±1.4 min for IELT, 9.5±3.7 for IIEF-5 and 14.1±4.5 for IPSS. Following the three-month daily 5mg tadalafil treatment, the scores were found to be 3.4±1.9 min, 16.1±4.7, and 10.4±3.8 for IELT, IIEF and IPSS, respectively. When the baseline and post-treatment scores were compared, a statistically significant increase was observed in the IELTs and IIEF-5 values whereas there was a significant decrease in IPSS (p<0.01). Conclusion A daily dose of 5mg tadalafil can be safely used in the treatment of erectile dysfunction and LUTS, that prolongs the ejaculatory latency time. PMID:27819758

Effect of tadalafil 5mg daily treatment on the ejaculatory times, lower urinary tract symptoms and erectile function in patients with erectile dysfunction.

PubMed

Karabakan, Mehmet; Keskin, Ercument; Akdemir, Serkan; Bozkurt, Aliseydi

2017-01-01

To investigate the effect of a 5mg daily tadalafil treatment on the ejaculation time, erectile function and lower urinary tract symptoms (LUTS) in patients with erectile dysfunction. A total of 60 patients diagnosed with erectile dysfunction were retrospectively evaluated using the international index of erectile function questionnaire-5 (IIEF-5), intravaginal ejaculatory latency time (IELT) and international prostate symptoms scores (IPSS). After the patients were treated with 5mg tadalafil once a day for three months, their erection, ejaculation and LUTS were assessed again. The fasting levels of blood glucose, total testosterone, low-density lipoprotein cholesterol, highdensity lipoprotein cholesterol and total cholesterol were measured. The independentsamples t-test was used to compare the pre- and post-treatment scores of the patients. The mean age of the 60 participants was 50.4±7.9 and the mean baseline serum total testosterone, total cholesterol, and fasting blood sugar were 444.6±178.6ng dL-1, 188.7±29.6mg/dL-1,104 (80-360) mg dL-1, respectively. The mean baseline scores were 2.2±1.4 min for IELT, 9.5±3.7 for IIEF-5 and 14.1±4.5 for IPSS. Following the three-month daily 5mg tadalafil treatment, the scores were found to be 3.4±1.9 min, 16.1±4.7, and 10.4±3.8 for IELT, IIEF and IPSS, respectively. When the baseline and post-treatment scores were compared, a statistically significant increase was observed in the IELTs and IIEF-5 values whereas there was a significant decrease in IPSS (p<0.01). A daily dose of 5mg tadalafil can be safely used in the treatment of erectile dysfunction and LUTS, that prolongs the ejaculatory latency time. Copyright® by the International Brazilian Journal of Urology.

Acute effects of the combination of sildenafil and inhaled treprostinil on haemodynamics and gas exchange in pulmonary hypertension.

PubMed

Voswinckel, Robert; Reichenberger, Frank; Enke, Beate; Kreckel, Andre; Krick, Stefanie; Gall, Henning; Schermuly, Ralph Theo; Grimminger, Friedrich; Rubin, Lewis J; Olschewski, Horst; Seeger, Werner; Ghofrani, Hossein A

2008-10-01

Inhaled treprostinil was recently developed for the treatment of pulmonary arterial hypertension (PAH). We investigated the safety and acute haemodynamic effects of the combination oral sildenafil and inhaled treprostinil in an open label study in patients with precapillary pulmonary hypertension. Inhaled nitric oxide (20ppm; n=50), sildenafil (50mg; n=50) and inhaled treprostinil (15microg; n=25 or 30microg; n=25) were applied in subsequent order during right heart catheter investigation to consecutive patients with pulmonary arterial hypertension (PAH; n=28), non-operable chronic thromboembolic pulmonary hypertension (CTEPH; n=17) and pulmonary fibrosis associated pulmonary hypertension (n=5). Inhaled nitric oxide reduced pulmonary vascular resistance (PVR) to 87.3+/-5.1% of baseline values, reduced mean pulmonary arterial pressure (PAP) to 89.7+/-3.5% and increased cardiac output (CO) to 102.4+/-2.9%. Sildenafil reduced PVR to 80.1+/-5.0%, mPAP to 86.5+/-2.9% and increased CO to 103.8+/-3.2%. Treprostinil, inhaled 1h after sildenafil, reduced PVR to 66.3+/-3.8%, mPAP to 77.8+/-3.3%, and increased CO to 107.1+/-3.3% (mean+/-95% confidence interval). Subgroup analysis showed similar acute haemodynamic effects in PAH and CTEPH patients. Ventilation/perfusion distribution measurement in six patients with pre-existing gas exchange limitations was not changed by sildenafil and treprostinil. Relevant side effects were not observed. The combination of sildenafil and inhaled treprostinil was well tolerated and induced additive, pulmonary selective vasodilatation in pulmonary hypertension patients. This could be of relevance also for long-term treatment of PAH and CTEPH patients.

Tadalafil in idiopathic or heritable pulmonary arterial hypertension (PAH) compared to PAH associated with connective tissue disease.

PubMed

Galiè, Nazzareno; Denton, Christopher P; Dardi, Fabio; Manes, Alessandra; Mazzanti, Gaia; Li, Baohui; Varanese, Lucio; Esler, Anne; Harmon, Cathi; Palazzini, Massimiliano

2017-05-15

The primary objective of this post hoc analysis was to evaluate clinical outcomes of tadalafil in patients with pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD-PAH) compared with patients with idiopathic/heritable PAH (I/H-PAH) for primary and key secondary efficacy endpoints, and safety. This analysis included adult patients with CTD-PAH or I/H-PAH who participated in the PHIRST and PHIRST-2 studies. Patients were randomized 1:1:1:1:1 to tadalafil (2.5, 10, 20, or 40mg) or placebo in the PHIRST study and the majority of these patients were subsequently assigned 40mg in PHIRST-2. Patients taking 20mg in PHIRST without demonstrating clinical worsening continued on 20mg in PHIRST-2. Outcomes analyzed included 6MWD, WHO-FC, and incidence and time to first occurrence of clinical worsening. Safety was assessed through evaluation of adverse events (AEs), clinical laboratory data, electrocardiograms, and physical examinations. Increased 6MWD in PHIRST was maintained in both CTD-PAH and I/H-PAH subgroups for 52weeks. Patients with CTD-PAH tended to be older, were more likely female, had lower exercise capacity, were more likely to have clinical worsening, and experienced AEs more frequently than patients with I/H-PAH. The effect of tadalafil treatment in patients enrolled in both PHIRST studies was detectable for both I/H-PAH and CTD-PAH subgroups. In general, subgroup differences were modest. Patients with CTD-PAH may perform less well than patients with I/H-PAH in safety and efficacy measures in all treatment groups, which is similar to other studies demonstrating a worse prognosis for patients with CTD-PAH. Copyright © 2017. Published by Elsevier B.V.

Vardenafil inhibiting parasympathetic function of tracheal smooth muscle.

PubMed

Lee, Fei-Peng; Chao, Pin-Zhir; Wang, Hsing-Won

2018-07-01

Levitra, a phosphodiesterase-5 (PDE5) inhibitor, is the trade name of vardenafil. Nowadays, it is applied to treatment of erectile dysfunction. PDE5 inhibitors are employed to induce dilatation of the vascular smooth muscle. The effect of Levitra on impotency is well known; however, its effect on the tracheal smooth muscle has rarely been explored. When administered for sexual symptoms via oral intake or inhalation, Levitra might affect the trachea. This study assessed the effects of Levitra on isolated rat tracheal smooth muscle by examining its effect on resting tension of tracheal smooth muscle, contraction caused by 10 -6  M methacholine as a parasympathetic mimetic, and electrically induced tracheal smooth muscle contractions. The results showed that adding methacholine to the incubation medium caused the trachea to contract in a dose-dependent manner. Addition of Levitra at doses of 10 -5  M or above elicited a significant relaxation response to 10 -6  M methacholine-induced contraction. Levitra could inhibit electrical field stimulation-induced spike contraction. It alone had minimal effect on the basal tension of the trachea as the concentration increased. High concentrations of Levitra could inhibit parasympathetic function of the trachea. Levitra when administered via oral intake might reduce asthma attacks in impotent patients because it might inhibit parasympathetic function and reduce methacholine-induced contraction of the tracheal smooth muscle. Copyright © 2018. Published by Elsevier Taiwan LLC.

Women taking the "blue pill" (sildenafil citrate): such a big deal?

PubMed

Lo Monte, Giuseppe; Graziano, Angela; Piva, Isabella; Marci, Roberto

2014-01-01

For years, phosphodiesterase type 5 inhibitors have been used for the treatment of erectile dysfunctions. Due to the similarities between male and female sexual response, several studies have assessed the effects of sildenafil citrate (Viagra(®)) in women affected by female sexual arousal disorder. The results are still conflicting and the drug is not devoid of adverse effects. Furthermore, female sexual arousal disorder is a heterogeneous condition whose underlying causes are difficult to diagnose and appropriate treatment requires a thorough sexual, psychological, and medical history along with specialist consultations. The clinician should pursue a global approach to the patient with sexual difficulties, while non-hormonal treatment such as phosphodiesterase type 5 inhibitors (ie, sildenafil citrate) should be kept as the last option.

Sildenafil Stimulates the Expression of Gaseous Monoxide-Generating Enzymes in Vascular Smooth Muscle Cells via Distinct Signaling Pathways

PubMed Central

Liu, Xiao-ming; Peyton, Kelly J.; Wang, Xinhui; Durante, William

2012-01-01

Sildenafil is a cGMP-specific phosphodiesterase type 5 inhibitor that augments cGMP accumulation following the activation of soluble guanylate cyclase (sGC). In this study, we investigated whether sildenafil promotes the production of the sGC-stimulatory gases, carbon monoxide and nitric oxide, by stimulating the expression of the inducible isoforms of heme oxygenase (HO-1) and nitric oxide synthase (iNOS) in vascular smooth muscle cells (SMCs). Sildenafil increased HO-1 expression and potentiated cytokine-mediated expression of iNOS and NO synthesis by SMCs. The induction of HO-1 was unaffected by the sGC inhibitor 1H-(1,2,4)oxadiazolo[4,3-α]quinozalin-1-one (ODQ) or the (9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindol91,2,3-fg:3′,2′,1′-kl)pyrrolo(3,4-i)benzodiazocine-10-carboxylic acid, methyl ester (KT 5823). However, the sildenafil-mediated increase in HO-1 promoter activity was abolished by mutating the antioxidant responsive elements in the promoter or by overexpressing a dominant-negative mutant of NF-E2-related factor-2 (Nrf2). Furthermore, the induction of HO-1 by sildenafil was accompanied by an increase in reactive oxygen species (ROS) and blocked by N-acetyl-L-cysteine and rotenone. In contrast, the enhancement of cytokine-stimulated NO synthesis by sildenafil was prevented by ODQ and the protein kinase A inhibitor (9S,10S,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo(1,2,3-fg:3′,2′,1′-kl)pyrrolo(3,4-i)(1,6)benzodiazocine-10-carboxylic acid hexyl ester (KT 5720) and duplicated by lipophilic analogues of cGMP. In conclusion, these studies demonstrate that sildenafil stimulates the expression of HO-1 and iNOS via the ROS-Nrf2 and sGC-cGMP pathway, respectively. The ability of sildenafil to block the catabolism of cGMP while stimulating the synthesis of sGC-stimulatory gaseous monoxides through the induction of HO-1 and iNOS provides a potent mechanism by which c

The novel functions of cGMP-specific phosphodiesterase 5 and its inhibitors in carcinoma cells and pulmonary/cardiovascular vessels.

PubMed

Zhu, Bing; Strada, Samuel J

2007-01-01

PDE5 is a key enzyme involved in the regulation of cGMP-specific signaling pathways in normal physiological processes such as smooth muscle contraction and relaxation. For this reason, inhibition of the enzyme can alter those pathophysiological conditions associated with a lowering cGMP level in tissues. For example, selective PDE5 inhibitors, such as sildenafil (Viagra, Pfizer), tadalafil (Cialis, Lilly-ICOS), and vardenafil (Levitra, Bayer), have been successfully used to treat the condition of human erectile dysfunction. More recently, the involvement of this enzyme has been proposed to influence antiproliferation and proapoptotic mechanism in multiple carcinomas. The data supporting this idea is based on increases in PDE5 activities in many carcinomas and the ability of PDE5 inhibitors such as exisulind and its analogs related to anticancer activities. Inhibition of PDE5 that results in sustained increases in [cGMP](i) are required to modify the process of apoptosis and mitotic arrest in those carcinoma cells with enhanced PDE5 expressions. Increases in PDE5 are also involved in contributing to the pathological changes in the pulmonary system resulting in hyper-proliferative remodeling of both smooth muscle and endothelium in models of pulmonary hypertension. For this reason, the use of PDE5 inhibitors in the treatment of human pulmonary hypertension has met with some success. The differences that we have previously noted in PDE isoenzymes in pulmonary arterial and microvascular endothelial cells may provide a more selective cellular strategy for use of such inhibitor. Additional studies on structure biology of these enzymes should lead to the development of agents with better cellular specificity than currently available drugs. Considering the enormous progress that has been made in the last few years, the future looks promising for agents affecting this enzyme and related systems.

PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy.

PubMed

Nelson, Michael D; Rader, Florian; Tang, Xiu; Tavyev, Jane; Nelson, Stanley F; Miceli, M Carrie; Elashoff, Robert M; Sweeney, H Lee; Victor, Ronald G

2014-06-10

To determine whether phosphodiesterase type 5 (PDE5) inhibition can alleviate exercise-induced skeletal muscle ischemia in boys with Duchenne muscular dystrophy (DMD). In 10 boys with DMD and 10 healthy age-matched male controls, we assessed exercise-induced attenuation of reflex sympathetic vasoconstriction, i.e., functional sympatholysis, a protective mechanism that matches oxygen delivery to metabolic demand. Reflex vasoconstriction was induced by simulated orthostatic stress, measured as the decrease in forearm muscle oxygenation with near-infrared spectroscopy, and performed when the forearm muscles were rested or lightly exercised with rhythmic handgrip exercise. Then, the patients underwent an open-label, dose-escalation, crossover trial with single oral doses of tadalafil or sildenafil. The major new findings are 2-fold: first, sympatholysis is impaired in boys with DMD-producing functional muscle ischemia-despite contemporary background therapy with corticosteroids alone or in combination with cardioprotective medication. Second, PDE5 inhibition with standard clinical doses of either tadalafil or sildenafil alleviates this ischemia in a dose-dependent manner. Furthermore, PDE5 inhibition also normalizes the exercise-induced increase in skeletal muscle blood flow (measured by Doppler ultrasound), which is markedly blunted in boys with DMD. These data provide in-human proof of concept for PDE5 inhibition as a putative new therapeutic strategy for DMD. This study provides Class IV evidence that in patients with DMD, PDE5 inhibition restores functional sympatholysis. © 2014 American Academy of Neurology.

Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest base camp: a randomized, double-blind, placebo-controlled crossover trial.

PubMed

Ghofrani, Hossein A; Reichenberger, Frank; Kohstall, Markus G; Mrosek, Eike H; Seeger, Timon; Olschewski, Horst; Seeger, Werner; Grimminger, Friedrich

2004-08-03

Alveolar hypoxia causes pulmonary hypertension and enhanced right ventricular afterload, which may impair exercise tolerance. The phosphodiesterase-5 inhibitor sildenafil has been reported to cause pulmonary vasodilatation. To investigate the effects of sildenafil on exercise capacity under conditions of hypoxic pulmonary hypertension. Randomized, double-blind, placebo-controlled crossover study. University Hospital Giessen, Giessen, Germany, and the base camp on Mount Everest. 14 healthy mountaineers and trekkers. Systolic pulmonary artery pressure, cardiac output, and peripheral arterial oxygen saturation at rest and during assessment of maximum exercise capacity on cycle ergometry 1) while breathing a hypoxic gas mixture with 10% fraction of inspired oxygen at low altitude (Giessen) and 2) at high altitude (the Mount Everest base camp). Oral sildenafil, 50 mg, or placebo. At low altitude, acute hypoxia reduced arterial oxygen saturation to 72.0% (95% CI, 66.5% to 77.5%) at rest and 60.8% (CI, 56.0% to 64.5%) at maximum exercise capacity. Systolic pulmonary artery pressure increased from 30.5 mm Hg (CI, 26.0 to 35.0 mm Hg) at rest to 42.9 mm Hg (CI, 35.6 to 53.5 mm Hg) during exercise in participants taking placebo. Sildenafil, 50 mg, significantly increased arterial oxygen saturation during exercise (P = 0.005) and reduced systolic pulmonary artery pressure at rest (P < 0.001) and during exercise (P = 0.031). Of note, sildenafil increased maximum workload (172.5 W [CI, 147.5 to 200.0 W]) vs. 130.6 W [CI, 108.8 to 150.0 W]); P < 0.001) and maximum cardiac output (P < 0.001) compared with placebo. At high altitude, sildenafil had no effect on arterial oxygen saturation at rest and during exercise compared with placebo. However, sildenafil reduced systolic pulmonary artery pressure at rest (P = 0.003) and during exercise (P = 0.021) and increased maximum workload (P = 0.002) and cardiac output (P = 0.015). At high altitude, sildenafil exacerbated existing headache

Nebulization performance of biodegradable sildenafil-loaded nanoparticles using the Aeroneb Pro: formulation aspects and nanoparticle stability to nebulization.

PubMed

Beck-Broichsitter, Moritz; Kleimann, Pia; Gessler, Tobias; Seeger, Werner; Kissel, Thomas; Schmehl, Thomas

2012-01-17

Polymeric nanoparticles meet the increasing interest for drug delivery applications and hold great promise to improve controlled drug delivery to the lung. Here, we present a series of investigations that were carried out to understand the impact of formulation variables on the nebulization performance of novel biodegradable sildenafil-loaded nanoparticles designed for targeted aerosol therapy of life-threatening pulmonary arterial hypertension. Narrowly distributed poly(D,L-lactide-co-glycolide) nanoparticles (size: ∼200 nm) were prepared by a solvent evaporation technique using poly(vinyl alcohol) (PVA) as stabilizer. The aerodynamic and output characteristics using the Aeroneb Pro nebulizer correlated well with the dynamic viscosity of the employed fluids for nebulization. The nebulization performance was mainly affected by the amount of employed stabilizer, rather than by the applied nanoparticle concentration. Nanoparticles revealed physical stability against forces generated during aerosolization, what is attributed to the adsorbed PVA layer around the nanoparticles. Sildenafil was successfully encapsulated into nanoparticles (encapsulation efficiency: ∼80%). Size, size distribution and sildenafil content of nanoparticles were not affected by nebulization and the in vitro drug release profile demonstrated a sustained sildenafil release over ∼120 min. The current study suggests that the prepared sildenafil-loaded nanoparticles are a promising pharmaceutical for the therapy of pulmonary arterial hypertension. Copyright © 2011 Elsevier B.V. All rights reserved.

Sildenafil protects against bile duct ligation induced hepatic fibrosis in rats: Potential role for silent information regulator 1 (SIRT1).

PubMed

Abd El Motteleb, Dalia M; Ibrahim, Islam A A E-H; Elshazly, Shimaa M

2017-11-15

Hepatic fibrosis is a potential health problem that may end with life-threatening cirrhosis and primary liver cancer. Recent studies point out to the protective effects of silent information regulator1 (SIRT1), against different models of organs fibrosis. This work aimed to investigate the possible protective effect of sildenafil (SIRT1 activator) against hepatic fibrosis induced by bile duct ligation (BDL). Firstly, three different doses of sildenafil (5, 10, 20mg/kg/day) were investigated; to detect the most protective one against BDL induced liver dysfunction and hepatic fibrosis. The most protective dose is then used; to study its effect on BDL induced SIRT1 downregulation, imbalance of oxidant/antioxidant status, increased inflammatory cytokines and fibrosis. Sildenafil (20mg/kg/day) was the most protective one, it caused upregulation of SIRT1, reduction of hepatic malondialdehyde (MDA) content, increase in expression of nuclear factor erythroid 2-related factor 2 (Nrf2), hemeoxygenease (HO)-1, reduced glutathione (GSH) content and superoxide dismutase (SOD) activity. Hepatic content of tumor necrosis factor-α (TNF-α) and nuclear factor κB (NFκB) expression & content displayed significant reductions with sildenafil treatment, Furthermore, sildenafil caused marked reductions of transforming growth factor (TGF)-β content, expression of plasminogen activator inhibitor-1 (PAI-1), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), α-smooth muscle actin (α-SMA), fibronectin, collagen I (α1) and hydroxyproline content. However, sildenafil protective effects were significantly reduced by co-administration of EX527 (SIRT1 inhibitor). Our work showed, for the first time that, sildenafil has promising protective effects against BDL induced liver dysfunction and hepatic fibrosis. These effects may be, in part, mediated by up regulation of SIRT1. Copyright © 2017. Published by Elsevier Inc.

[Efficacy of sildenafil citrate in men with erectile dysfunction following bilateral nerve-sparing radical prostatectomy: systematic review and meta-analysis].

PubMed

Lu, Xinxing; Han, Hu; Xing, Nianzeng; Tian, Long

2015-09-22

To systematically assess the efficacy and safety of oral sildenafil citrate for post bilateral nerve-sparig radical prostatectomy (post-BNSRP) erectile dysfunction (ED). The following keywords: sildenafil, radical prostatectomy were used to search in Medline, Pubmed, Web of Science, Cochrane Library, CNKI, WanFang Database. The title, abstract and keywords of each article were independently screened by two reviewers. Randomized controlled trials (RCT) published between 1990 and 2014 were retrieved according to our inclusion and exclusion criteria. The efficacy and safety of oral sildenafil citrate for post-BNSRP ED were systematically assessed by meta-analysis. Four RCTs with 320 cases were included after literature retrieval and filtering. The potency rates were 32.1% (35/109) and 11.3% (7/62) between sildenafil and placebo groups after meta-analysis and showed statistically significant differences (OR = 4.66, 95% CI: 1.79-12.11). IIEF-5 score in sildenafil group was significant higher than that in the placebo group (WMD: 4.73, 95% CI: 3.26-6.19). In subgroup meta-analysis, the potency rates in high-dose, low-dose sildenafil groups and placebo groups were 30.4% (14/46), 25.0% (10/40) and 4.5% (2/44), respectively. There were statistically significant differences between the high-dose subgroup and placebo group (OR = 9.32, 95% CI: 1.96-44.23), and the low-dose subgroup and placebo group (OR = 6.99, 95% CI: 1.43-34.22). But there was no significant difference between high-dose and low-dose subgroups (OR = 1.31, 95% CI: 0.51-3.40). Compared with placebo, sildenafil has considerable efficacy for erectile function rehabilitationas as a primary treatment for post-BNSRP ED. There is no significant difference between high-dose and low-dose schedule for its efficacy. However, further studies are required to optimize treatment.

Long-term treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial hypertension.

PubMed

Michelakis, Evangelos D; Tymchak, Wayne; Noga, Michelle; Webster, Linda; Wu, Xi-Chen; Lien, Dale; Wang, Shao-Hua; Modry, Dennis; Archer, Stephen L

2003-10-28

The prognosis and functional capacity of patients with pulmonary arterial hypertension (PAH) is poor, and there is a need for safe, effective, inexpensive oral treatments. A single dose of sildenafil, an oral phosphodiesterase type-5 (PD-5) inhibitor, is an effective and selective pulmonary vasodilator in PAH. However, the long-term effects of PD-5 inhibition and its mechanism of action in human pulmonary arteries (PAs) are unknown. We hypothesized that 3 months of sildenafil (50 mg orally every 8 hours) added to standard treatment would be safe and improve functional capacity and hemodynamics in PAH patients. We studied 5 consecutive patients (4 with primary pulmonary hypertension, 1 with Eisenmenger's syndrome; New York Heart Association class II to III). Functional class improved by > or =1 class in all patients. Pretreatment versus posttreatment values (mean+/-SEM) were as follows: 6-minute walk, 376+/-30 versus 504+/-27 m, P<0.0001; mean PA pressure, 70+/-3 versus 52+/-3 mm Hg, P<0.007; pulmonary vascular resistance index 1702+/-151 versus 996+/-92 dyne x s x cm(-5) x m(-2), P<0.006. The systemic arterial pressure was unchanged, and no adverse effects occurred. Sildenafil also reduced right ventricular mass measured by MRI. In 7 human PAs (6 cardiac transplant donors and 1 patient with PAH on autopsy), we showed that PD-5 is present in PA smooth muscle cells and that sildenafil causes relaxation by activating large-conductance, calcium-activated potassium channels. This small pilot study suggests that long-term sildenafil therapy might be a safe and effective treatment for PAH. At a monthly cost of 492 dollars Canadian, sildenafil is more affordable than most approved PAH therapies. A large multicenter trial is indicated to directly compare sildenafil with existing PAH treatments.

Effect of L-arginine and sildenafil citrate on intrauterine growth restriction fetuses: a meta-analysis.

PubMed

Chen, Juncao; Gong, Xiaoyuan; Chen, Pingyang; Luo, Kaiju; Zhang, Xiuquan

2016-08-16

Intrauterine growth restriction (IUGR) is associated with perinatal morbidity and mortality. Several clinical trials have reported L-arginine and sildenafil citrate had effect on intrauterine growth restriction fetuses. A meta-analysis of available randomized controlled trials (RCTs) was conducted to investigate the effects of L-arginine and sildenafil citrate on major clinical outcomes of IUGR fetuses. Systematically searched Medline, Embase, the Cochrane Library, and Clinical Trials, references of retrieved articles, and conference proceedings from 1960 to 2015. We included randomized controlled trials assessing the effects of L-arginine and sildenafil citrate on IUGR. Outcomes analyzed were the birth weight, gestational age at labor, Apgar score at 1and 5 min, the ratio of NRDS, the ratio of ICH and neonatal death, etc. Ten trials were included. Nine trials (576 patients) compared L-arginine with either placebo or no intervention. In the L-arginine treatment groups of the L-arginine trials, there was a significant increase in fetal birth weight (SMD 0.41, 95 % CI [0.24,0.58]), gestational age (SMD 0.30, 95 % CI [0.07,0.54]); L-arginine treatment group have a significant reduction in the ratio of neonatal respiratory distress syndrome (P = 0.009), intracranial hemorrhage of fetuses (P = 0.002), but the number of included studies and people on these outcomes are small. As only one trial (41 patients) compared sildenafil citrate with placebo, it was too small for reliable conclusions about possible differential effects could be drawn. The results of this meta-analysis showed that L-arginine increased birth weight and prolonged gestational age at labor of IUGR fetuses. However, further large-scale RCTs are needed to adequately assess the effect of L-arginine and Sildenafil citrate on clinical outcomes, because the number of study may be small.

Efficacy and safety of tadalafil 5 mg once daily in the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia in men aged ≥75 years: integrated analyses of pooled data from multinational, randomized, placebo-controlled clinical studies.

PubMed

Oelke, Matthias; Wagg, Adrian; Takita, Yasushi; Büttner, Hartwig; Viktrup, Lars

2017-05-01

To assess efficacy and safety of tadalafil in men aged ≥75 years with lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) and additional safety in men aged ≥75 years with erectile dysfunction (ED). We conducted an integrated analysis of 12 phase II-III randomized, double-blind and/or open-label extension studies to evaluate short-term (12-26 weeks) efficacy and short- and longer-term (42-52 weeks) safety in men aged <75 years vs men aged ≥75 years. All men received once-daily tadalafil 5 mg or placebo. The efficacy outcome was International Prostate Symptom Score (IPSS). Safety measurements included treatment-emergent adverse events (TEAEs), adverse events (AEs) leading to discontinuation, serious AEs (SAEs), and cardiovascular AEs. All analyses were intention-to-treat. Changes from baseline to efficacy endpoint and differences in changes between treatment groups were estimated as least-squares means using analysis of covariance models. Change in the mean IPSS was significantly different in men aged <75 years vs those aged ≥75 years across tadalafil and placebo groups (treatment-by-age interaction P = 0.034). Tadalafil was not statistically significantly better than placebo in men aged ≥75 years, but effect size varied between studies. Maintenance of efficacy with tadalafil was observed across age groups. Short-term tadalafil safety findings for men aged <75 vs ≥75 years included: TEAEs (52 [33.8%] vs 503 [30.1%]), AEs leading to discontinuation (3 [1.9%] vs 50 [3.0%]), SAEs (4 [2.6%] vs 15 [0.9%]) and cardiovascular AEs (4 [2.6%] vs 30 [1.8%]). Long-term tadalafil safety data did not reveal clinically relevant differences between age groups. Limitations include exclusion of men with serious co-existing conditions and limited sample sizes of men aged ≥75 years. Efficacy with once-daily tadalafil 5 mg in the treatment of LUTS/BPH differed between men aged <75 vs ≥75 years, with significant efficacy in the <75-year age

Quantification of active pharmaceutical ingredient and impurities in sildenafil citrate obtained from the Internet.

PubMed

Veronin, Michael A; Nutan, Mohammad T; Dodla, Uday Krishna Reddy

2014-10-01

The accessibility of prescription drugs produced outside of the United States, most notably sildenafil citrate (innovator product, Viagra®), has been made much easier by the Internet. Of greatest concern to clinicians and policymakers is product quality and patient safety. The US Food and Drug Administration (FDA) has issued warnings to potential buyers that the safety of drugs purchased from the Internet cannot be guaranteed, and may present a health risk to consumers from substandard products. The objective of this study was to determine whether generic sildenafil citrate tablets from international markets obtained via the Internet are equivalent to the US innovator product regarding major aspects of pharmaceutical quality: potency, accuracy of labeling, and presence and level of impurities. This will help identify aspects of drug quality that may impact public health risks. A total of 15 sildenafil citrate tablets were obtained for pharmaceutical analysis: 14 generic samples from international Internet pharmacy websites and the US innovator product. According to US Pharmacopeial guidelines, tablet samples were tested using high-performance liquid chromatography for potency of active pharmaceutical ingredient (API) and levels of impurities (impurities A, B, C, and D). Impurity levels were compared with International Conference on Harmonisation (ICH) limits. Among the 15 samples, 4 samples possessed higher impurity B levels than the ICH qualification threshold, 8 samples possessed higher impurity C levels than the ICH qualification threshold, and 4 samples possessed more than 1% impurity quantity of maximum daily dose (MDD). For API, 6 of the samples failed to fall within the 5% assay limit. Quality assurance tests are often used to detect formulation defects of drug products during the manufacturing and/or storage process. Results suggest that manufacturing standards for sildenafil citrate generic drug products compared with the US innovator product are not

Quantification of active pharmaceutical ingredient and impurities in sildenafil citrate obtained from the Internet

PubMed Central

Nutan, Mohammad T.; Dodla, Uday Krishna Reddy

2014-01-01

Background: The accessibility of prescription drugs produced outside of the United States, most notably sildenafil citrate (innovator product, Viagra®), has been made much easier by the Internet. Of greatest concern to clinicians and policymakers is product quality and patient safety. The US Food and Drug Administration (FDA) has issued warnings to potential buyers that the safety of drugs purchased from the Internet cannot be guaranteed, and may present a health risk to consumers from substandard products. Objective: The objective of this study was to determine whether generic sildenafil citrate tablets from international markets obtained via the Internet are equivalent to the US innovator product regarding major aspects of pharmaceutical quality: potency, accuracy of labeling, and presence and level of impurities. This will help identify aspects of drug quality that may impact public health risks. Methods: A total of 15 sildenafil citrate tablets were obtained for pharmaceutical analysis: 14 generic samples from international Internet pharmacy websites and the US innovator product. According to US Pharmacopeial guidelines, tablet samples were tested using high-performance liquid chromatography for potency of active pharmaceutical ingredient (API) and levels of impurities (impurities A, B, C, and D). Impurity levels were compared with International Conference on Harmonisation (ICH) limits. Results: Among the 15 samples, 4 samples possessed higher impurity B levels than the ICH qualification threshold, 8 samples possessed higher impurity C levels than the ICH qualification threshold, and 4 samples possessed more than 1% impurity quantity of maximum daily dose (MDD). For API, 6 of the samples failed to fall within the 5% assay limit. Conclusions: Quality assurance tests are often used to detect formulation defects of drug products during the manufacturing and/or storage process. Results suggest that manufacturing standards for sildenafil citrate generic drug

Sildenafil (Viagra) and club drug use in gay and bisexual men: the role of drug combinations and context.

PubMed

Halkitis, Perry N; Green, Kelly A

2007-06-01

Data ascertained in a study of club drug use among 450 gay and bisexual men indicate that at least one class of PDE-5 (phosphodiesterase type 5 inhibitor, sildenafil [Viagra]) is used frequently in combination with club drugs such as methamphetamine, MDMA (3,4 methylenedioxymethamphetamine [ecstasy]), ketamine, cocaine, and GHB (gamma hydroxy butyrate). Patterns of sildenafil use in combination with each of the club drugs differ among key demographics including race and age. Multivariate models, controlling for demographic factors, suggest that contextual factors are key to understanding why men mix sildenafil with club drugs, although age may still be an important issue to consider. Of particular importance is the fact that use of club drugs in combination with sildenafil is strongly associated with circuit and sex parties, where a centerpiece of these environments focuses on sexual exchange. These models imply interplay between person-level and contextual factors in explaining drug use patterns and further indicate that interventions aimed at addressing illicit substance use must carefully consider the role of environmental factors in explaining behavior.

Involvement of AMPK, IKβα-NFκB and eNOS in the sildenafil anti-inflammatory mechanism in a demyelination model.

PubMed

Nunes, Ana Karolina Santana; Rapôso, Catarina; Rocha, Sura Wanessa Santos; Barbosa, Karla Patrícia de Sousa; Luna, Rayana Leal de Almeida; da Cruz-Höfling, Maria Alice; Peixoto, Christina Alves

2015-11-19

Sildenafil (Viagra®) has recently been found to have a neuroprotective effect, which occurs through the inhibition of inflammation and demyelination in the cerebellum. However, the mechanism of action of sildenafil remains unknown. AMPK, the regulatory protein of the lipid and glucose metabolism, plays a protective role by activating the eNOS enzyme. The production of a nanomolar concentration of NO by eNOS has an anti-inflammatory effect through the cGMP signaling pathway and plays an important role in the regulation of the nuclear transcription factor (NFkB), preventing the expression of inflammatory genes. The present study investigated whether AMPK-eNOS-NO-cGMP-IКβα-NFkB is involved in the mechanism of action of sildenafil in a cuprizone-demyelination model. Neuroinflammation and demyelination induced by cuprizone in rodents have been widely used as a model of MS. In the present study, five male C57BL/6 mice (7-10 weeks old) were used. Over a four week period, the groups received: cuprizone (CPZ) 0.2% mixed in feed; CPZ in the diet, combined with the administration of sildenafil (Viagra®, Pfizer, 25mg/kg) orally in drinking water, starting concurrently (sild-T0) or 15 days (sild-T15) after the start of CPZ. Control animals received pure food and water. The cerebella of the mice were dissected and processed for immunohistochemistry, immunofluorescence (frozen), western blotting and dosage of cytokines (Elisa). CPZ induced an increase in the expression of GFAP, IL-1β TNF-α, total NFkB and inactive AMPK, and prompt microglia activation. CPZ also induced a reduction of IKβα. The administration of sildenafil reduced the expression of the pro-inflammatory cytokines IL-1β and TNF-α and increased the expression of the anti-inflammatory cytokine IL-10. In addition, the administration of sildenafil reduced expression of GFAP, NFkB, inactive AMPK and iNOS, and increased IKβα. Interestingly, sildenafil also reduced levels of NGF. In general, the sild-T0 group

Identification of a new tadalafil analogue, N-3-hydroxypropylnortadalafil, in a supplement product.

PubMed

Lee, Hui-Chun; Lin, Yun-Lian; Huang, Yen-Chun; Tsai, Chia-Fen; Wang, Der-Yuan

2018-06-01

A novel tadalafil analogue, which exhibits similarity to 2-hydroxypropylnortadalafil, was found in dietary supplements using adulterants screening and isolated using column chromatography. By using extensive 1D- and 2D-NMR and MS spectral analyses, the structure was determined as 6-(1,3-Benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-(3-hydroxypropyl)pyrazino(1',2':1,6)pyrido(3,4-b)indole-1,4-dione, and the analogue was named N-3-hydroxypropylnortadalafil. Copyright © 2018 Elsevier B.V. All rights reserved.

Cytogenetic effects of sildenafil citrate (Viagra) on SWR/J mouse bone marrow cells.

PubMed

Abou-Tarboush, Faisal Mohamed; Abdel-Samad, Mohamed Fathy

2010-10-01

The present study was conducted to investigate the cytogenetic effects of sildenafil citrate in SWR/J mouse bone marrow cells. Thirty-six males and 36 females were used and divided into four groups. Each group contained 18 animals (9 males and 9 females), weighing 30-35 g. These animals were orally administered with a single dose of 13, 26 or 40 mg/kg sildenafil citrate solution. A control group received normal saline in an identical condition. The animals were sacrificed at 12, 24 or 48 h, after the treatment. Chromosome aberrations were investigated in 50 metaphases per animal. No significant differences in the percentages of mitotic indices or in the frequencies of chromosome aberrations were observed between treated male and female mice at any doses or at any time intervals used, therefore, data from the two sexes were pooled when analyzed statistically. No significant (p < 0.05) differences in the percentages of mitotic indices or in the frequencies of chromosome aberrations were observed between sildenafil citrate-treated groups and the control group at any doses or at any time intervals used. However, the percentages of centromeric adhesions increased significantly (p < 0.01) in treated groups as compared with the control group at all doses and at all time intervals used. In conclusion, the results of the present study suggest that sildenafil citrate does not have cytogenetic effects on mouse bone marrow cells, but the centromeric adhesions induced by this drug need further studies to confirm them and to investigate the possible mechanism(s) responsible for such effect.

Cytogenetic effects of sildenafil citrate (Viagra) on SWR/J mouse bone marrow cells

PubMed Central

Abou-Tarboush, Faisal Mohamed; Abdel-Samad, Mohamed Fathy

2010-01-01

The present study was conducted to investigate the cytogenetic effects of sildenafil citrate in SWR/J mouse bone marrow cells. Thirty-six males and 36 females were used and divided into four groups. Each group contained 18 animals (9 males and 9 females), weighing 30–35 g. These animals were orally administered with a single dose of 13, 26 or 40 mg/kg sildenafil citrate solution. A control group received normal saline in an identical condition. The animals were sacrificed at 12, 24 or 48 h, after the treatment. Chromosome aberrations were investigated in 50 metaphases per animal. No significant differences in the percentages of mitotic indices or in the frequencies of chromosome aberrations were observed between treated male and female mice at any doses or at any time intervals used, therefore, data from the two sexes were pooled when analyzed statistically. No significant (p < 0.05) differences in the percentages of mitotic indices or in the frequencies of chromosome aberrations were observed between sildenafil citrate-treated groups and the control group at any doses or at any time intervals used. However, the percentages of centromeric adhesions increased significantly (p < 0.01) in treated groups as compared with the control group at all doses and at all time intervals used. In conclusion, the results of the present study suggest that sildenafil citrate does not have cytogenetic effects on mouse bone marrow cells, but the centromeric adhesions induced by this drug need further studies to confirm them and to investigate the possible mechanism(s) responsible for such effect. PMID:23961094

Treatment of erectile dysfunction with sildenafil citrate in renal allograft recipients: a randomized, double-blind, placebo-controlled, crossover trial.

PubMed

Sharma, Raj K; Prasad, Narayan; Gupta, Amit; Kapoor, Rakesh

2006-07-01

Erectile dysfunction (ED) is observed frequently in patients with end-stage renal disease, hemodialysis patients, and renal allograft recipients. There are few studies of sildenafil use in renal allograft recipients. The study is designed as a randomized, double-blind, placebo-controlled, crossover trial. Efficacy was assessed by using the self-administered International Index of Erectile Function (IIEF), a 15-question validated measure of ED, and a global efficacy question (Did the treatment improve your erection?). Thirty-two eligible renal transplant recipients were included in this study. After treatment with sildenafil citrate, patients had significantly better scores in 13 of 15 questions, except for questions 11 (desire frequency; P = 0.39) and 12 (desire level; P = 0.61). Treatment efficacy assessed through questions 3 (penetration ability; P < 0.001) and 4 (maintenance frequency; P < 0.001) was significantly better after sildenafil therapy. There were no significant differences between baseline and post-placebo treatment scores, except for question 13 (relationship satisfaction). Patients treated with sildenafil had significantly better scores in 4 domains compared with baseline, but a difference was not observed in the sexual desire domain (P = 0.32). There were no significant differences in scores between placebo and baseline in any domain. On the global efficacy question, 81.3% of patients showed improvement compared with 18.7% with placebo. There were no differences in areas under the curve and maximum cyclosporine concentrations before and after sildenafil therapy. No patient discontinued the drug because of side effects except for 1 patient with visual hallucination. Treatment with sildenafil in renal transplant recipients is a valid option with an effective response.

The effects of sildenafil and n-acetylcysteine on ischemia and reperfusion injury in gastrocnemius muscle and femoral artery endothelium.

PubMed

Aksu, Volkan; Yüksel, Volkan; Chousein, Serchat; Taştekin, Ebru; İşcan, Şahin; Sağiroğlu, Gönül; Canbaz, Suat; Sunar, Hasan

2015-02-01

We aimed to examine the effects of sildenafil and n-acetylcystein on ischemia/reperfusion injury in femoral artery endothelium and gastrocnemius muscle. 32 rats of Sprague-Dawley breed were randomly divided into four groups (n=8). Median laparotomy was performed, then a 120-minute ischemia was created by microvascular clamping of infrarenal aorta, followed by the release of clamping. In sildenafil group, 1 mg/kg of sildenafil infusion and in the n-acetylcystein group, 100 mg/kg of n-acetylcystein infusion was administered after release of clamps. Blood samples and tissue samples of femoral artery and gastrocnemius muscle were extracted for a histopathological evaluation. Serum levels of malondialdehyde in ischemia/reperfusion group (6.16±0.79) were higher compared to the control group (4.69±0.33), whereas a significant decrease was detected in sildenafil (5.17±0.50) and n-acetylcystein (4.96±0.49) groups. Femoral artery tissue sections of the control group, mean tumor necrosis factor alpha and hypoxy-induced factor-1 alpha immunoreactivity were found to be negative. In the ischemia/reperfusion group, mean tumor necrosis factor α immunoreactivity was intense and mean hypoxy-induced factor-1 alpha immunoreactivity was 51-75%. In the ischemia/reperfusion+Sildenafil and ischemia/reperfusion+NAS groups, mean tumor necrosis factor α immunoreactivity was slight and mean hypoxy-induced factor-1 alpha immunoreactivity was 26-50%. In conclusion, sildenafil and n-acetylcystein may reduce femoral artery endothelium and gastrocnemius muscle injury following lower extremity ischemia/reperfusion. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Evaluation of the effects of sildenafil citrate (viagra) on vertebral artery blood flow in patients with vertebro-basilar insufficiency.

PubMed

Bozgeyik, Zulkif; Berilgen, Sait; Ozdemir, Huseyin; Tekatas, Aslan; Ogur, Erkin

2008-01-01

To investigate the effects of sildenafil citrate (Viagra) on the vertebral artery blood flow of patients with vertebro-basilar insufficiency (VBI) using color duplex sonography (CDS). The study included 21 patients with VBI (aged 31-76; mean 61.0 +/- 10.5 yrs). We administered a 50 mg oral dose of sildenafil citrate to all patients. Next, we measured the peak systolic velocity (Vmax), end diastolic velocity (Vmin), resistive index (RI), pulsatility index (PI), diameter, area, and flow volume (FV) of vertebral arteries using CDS before the administration of sildenafil citrate; 45 minutes after, and 75 minutes after administration. Statistical testing was performed using SPSS for windows version 11.0. The statistical test used to determine the outcome of the analysis was the repeated measures analysis of variance (ANOVA) test. Compared to the baseline values, the vertebral artery diameter, area, and FV increased significantly following the administration of sildenafil citrate. The diameter, area and FV increased from 3.39 mm at 45 minutes to 3.64 mm at 75 minutes, 9.43 cm(2) to 10.80 cm(2) at 45 minutes and 10.81 cm(2) at 75 minutes, as well as from 0.07 L/min at baseline to 0.09 L/min at 45 minutes and unchanged at 75 minutes, respectively. Sildenafil citrate elicited a significant effect on vertebral artery diameter, area and FVs.

Comparison between transdermal nitroglycerin and sildenafil citrate in intrauterine growth restriction: effects on uterine, umbilical and fetal middle cerebral artery pulsatility indices.

PubMed

Trapani, A; Gonçalves, L F; Trapani, T F; Franco, M J; Galluzzo, R N; Pires, M M S

2016-07-01

To evaluate the effects of transdermal nitroglycerin (GTN) and sildenafil citrate on Doppler velocity waveforms of the uterine (UtA), umbilical (UA) and fetal middle cerebral (MCA) arteries in pregnancies with intrauterine growth restriction (IUGR). This was a prospective study of 35 singleton pregnancies (gestational age, 24-31 weeks) with IUGR and abnormal UtA and UA Doppler waveforms. We compared maternal arterial blood pressure and Z-scores of the pulsatility index (PI) of UtA, UA and fetal MCA before and after application of a transdermal GTN patch (average dose, 0.4 mg/h), oral sildenafil citrate (50 mg) or placebo. Statistical analysis was performed by ANOVA for paired samples. There was a significant decrease in UtA-PI after application of GTN (21.0%) and sildenafil citrate (20.4%). A significant reduction in UA-PI was also observed for both GTN (19.1%) and sildenafil citrate (18.2%). There was no difference in UtA- and UA-PI when the GTN and sildenafil groups were compared. No changes in Doppler velocimetry were observed in the placebo group and no significant change in MCA-PI was observed in any group. Maternal arterial blood pressure decreased with administration of both GTN and sildenafil citrate in those with pre-eclampsia. The use of transdermal GTN or sildenafil citrate in pregnancies with IUGR is associated with a significant reduction in both UtA and UA Doppler PI, as well as maternal arterial blood pressure. Neither drug affected the MCA-PI. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Sildenafil has little influence on cardiovascular hemodynamics or 6-km time trial performance in trained men and women at simulated high altitude.

PubMed

Jacobs, Kevin A; Kressler, Jochen; Stoutenberg, Mark; Roos, Bernard A; Friedlander, Anne L

2011-01-01

Sildenafil improves maximal exercise capacity at high altitudes (∼4350-5800 m) by reducing pulmonary arterial pressure and enhancing oxygen delivery, but the effects on exercise performance at less severe altitudes are less clear. To determine the effects of sildenafil on cardiovascular hemodynamics (heart rate, stroke volume, and cardiac output), arterial oxygen saturation (SaO2), and 6-km time-trial performance of endurance-trained men and women at a simulated altitude of ∼3900 m. Twenty men and 15 women, endurance-trained, completed one experimental exercise trial (30 min at 55% of altitude-specific capacity +6-km time trial) at sea level (SL) and two trials at simulated high altitude (HA) while breathing hypoxic gas (12.8% FIo2) after ingestion of either placebo or 50 mg sildenafil in double-blind, randomized, and counterbalanced fashion. Maximal exercise capacity and SaO2 were significantly reduced at HA compared to SL (18%-23%), but sildenafil did not significantly improve cardiovascular hemodynamics or time-trial performance in either men or women compared to placebo and only improved SaO2 in women (4%). One male subject (5% of male subjects, 2.8% of all subjects) exhibited a meaningful 36-s improvement in time-trial performance with sildenafil compared to placebo. In this group of endurance trained men and women, sildenafil had very little influence on cardiovascular hemodynamics, SaO2, and 6-km time-trial performance at a simulated altitude of ∼3900 m. It appears that a very small percentage of endurance-trained men and women derive meaningful improvements in aerobic performance from sildenafil at a simulated altitude of ∼3900 m.

Women taking the “blue pill” (sildenafil citrate): such a big deal?

PubMed Central

Lo Monte, Giuseppe; Graziano, Angela; Piva, Isabella; Marci, Roberto

2014-01-01

For years, phosphodiesterase type 5 inhibitors have been used for the treatment of erectile dysfunctions. Due to the similarities between male and female sexual response, several studies have assessed the effects of sildenafil citrate (Viagra®) in women affected by female sexual arousal disorder. The results are still conflicting and the drug is not devoid of adverse effects. Furthermore, female sexual arousal disorder is a heterogeneous condition whose underlying causes are difficult to diagnose and appropriate treatment requires a thorough sexual, psychological, and medical history along with specialist consultations. The clinician should pursue a global approach to the patient with sexual difficulties, while non-hormonal treatment such as phosphodiesterase type 5 inhibitors (ie, sildenafil citrate) should be kept as the last option. PMID:25422584

1H, 13C, 15N NMR analysis of sildenafil base and citrate (Viagra) in solution, solid state and pharmaceutical dosage forms.

PubMed

Wawer, Iwona; Pisklak, Maciej; Chilmonczyk, Zdzisław

2005-08-10

Sildenafil citrate (SC) (Viagra) and sildenafil base in pure form are easily and unequivocally characterized by multinuclear NMR spectroscopy. Analysis of chemical shifts indicates that: (i) N6-H forms intramolecular hydrogen bonds, (ii) N25 is protonated in the salt and (iii) intermolecular OH...N hydrogen bonds involving N2 and N4 are present in the solid sildenafil citrate. 13C CPMAS NMR method has been proposed for the identification and quantitation of Viagra in its pharmaceutical formulations.

Sildenafil reduces respiratory muscle weakness and fibrosis in the mdx mouse model of Duchenne muscular dystrophy.

PubMed

Percival, Justin M; Whitehead, Nicholas P; Adams, Marvin E; Adamo, Candace M; Beavo, Joseph A; Froehner, Stanley C

2012-09-01

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy caused by mutations in the dystrophin gene. Loss of dystrophin initiates a progressive decline in skeletal muscle integrity and contractile capacity which weakens respiratory muscles including the diaphragm, culminating in respiratory failure, the leading cause of morbidity and mortality in DMD patients. At present, corticosteroid treatment is the primary pharmacological intervention in DMD, but has limited efficacy and adverse side effects. Thus, there is an urgent need for new safe, cost-effective, and rapidly implementable treatments that slow disease progression. One promising new approach is the amplification of nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signalling pathways with phosphodiesterase 5 (PDE5) inhibitors. PDE5 inhibitors serve to amplify NO signalling that is attenuated in many neuromuscular diseases including DMD. We report here that a 14-week treatment of the mdx mouse model of DMD with the PDE5 inhibitor sildenafil (Viagra(®), Revatio(®)) significantly reduced mdx diaphragm muscle weakness without impacting fatigue resistance. In addition to enhancing respiratory muscle contractility, sildenafil also promoted normal extracellular matrix organization. PDE5 inhibition slowed the establishment of mdx diaphragm fibrosis and reduced matrix metalloproteinase-13 (MMP-13) expression. Sildenafil also normalized the expression of the pro-fibrotic (and pro-inflammatory) cytokine tumour necrosis factor α (TNFα). Sildenafil-treated mdx diaphragms accumulated significantly less Evans Blue tracer dye than untreated controls, which is also indicative of improved diaphragm muscle health. We conclude that sildenafil-mediated PDE5 inhibition significantly reduces diaphragm respiratory muscle dysfunction and pathology in the mdx mouse model of Duchenne muscular dystrophy. This study provides new insights into the therapeutic utility of targeting defects in NO

Tadalafil once daily and extracorporeal shock wave therapy in the management of patients with Peyronie's disease and erectile dysfunction: results from a prospective randomized trial.

PubMed

Palmieri, A; Imbimbo, C; Creta, M; Verze, P; Fusco, F; Mirone, V

2012-04-01

Extracorporeal shock wave therapy improves erectile function in patients with Peyronie's disease. However, erectile dysfunction still persists in many cases. We aimed to investigate the effects of extracorporeal shock wave therapy plus tadalafil 5 mg once daily in the management of patients with Peyronie's disease and erectile dysfunction not previously treated. One hundred patients were enrolled in a prospective, randomized, controlled study. Patients were randomly allocated to receive either extracorporeal shock wave therapy alone for 4 weeks (n = 50) or extracorporeal shock wave therapy plus tadalafil 5 mg once daily for 4 weeks (n = 50). Main outcome measures were: erectile function (evaluated through the shortened version of the International Index of Erectile Function), pain during erection (evaluated through a Visual Analog Scale), plaque size, penile curvature and quality of life (evaluated through an internal questionnaire). Follow-up evaluations were performed after 12 and 24 weeks. In both groups, at 12 weeks follow-up, mean Visual Analog Scale score, mean International Index of Erectile Function score and mean quality of life score ameliorated significantly while mean plaque size and mean curvature degree were unchanged. Intergroup analysis revealed a significantly higher mean International Index of Erectile Function score and quality of life score in patients receiving the combination. After 24 weeks, intergroup analysis revealed a significantly higher mean International Index of Erectile Function score and mean quality of life score in patients that received extracorporeal shock wave therapy plus tadalafil. In conclusion extracorporeal shock wave therapy plus tadalafil 5 mg once daily may represent a valid conservative strategy for the management of patients with Peyronie's disease and erectile dysfunction. © 2011 The Authors. International Journal of Andrology © 2011 European Academy of Andrology.

Ups and Downs of Viagra: Revisiting Ototoxicity in the Mouse Model

PubMed Central

Au, Adrian; Stuyt, John Gerka; Chen, Daniel; Alagramam, Kumar

2013-01-01

Sildenafil citrate (Viagra), a phosphodiesterase 5 inhibitor (PDE5i), is a commonly prescribed drug for erectile dysfunction. Since the introduction of Viagra in 1997, several case reports have linked Viagra to sudden sensorineural hearing loss. However, these studies are not well controlled for confounding factors, such as age and noise-induced hearing loss and none of these reports are based on prospective double-blind studies. Further, animal studies report contradictory data. For example, one study (2008) reported hearing loss in rats after long-term and high-dose exposure to sildenafil citrate. The other study (2012) showed vardenafil, another formulation of PDE5i, to be protective against noise-induced hearing loss in mice and rats. Whether or not clinically relevant doses of sildenafil citrate cause hearing loss in normal subjects (animals or humans) is controversial. One possibility is that PDE5i exacerbates age-related susceptibility to hearing loss in adults. Therefore, we tested sildenafil citrate in C57BL/6J, a strain of mice that displays increased susceptibility to age-related hearing loss, and compared the results to those obtained from the FVB/N, a strain of mice with no predisposition to hearing loss. Six-week-old mice were injected with the maximum tolerated dose of sildenafil citrate (10 mg/kg/day) or saline for 30 days. Auditory brainstem responses (ABRs) were recorded pre- and post injection time points to assess hearing loss. Entry of sildenafil citrate in the mouse cochlea was confirmed by qRT-PCR analysis of a downstream target of the cGMP-PKG cascade. ABR data indicated no statistically significant difference in hearing between treated and untreated mice in both backgrounds. Results show that the maximum tolerated dose of sildenafil citrate administered daily for 4 weeks does not affect hearing in the mouse. Our study gives no indication that Viagra will negatively impact hearing and it emphasizes the need to revisit the issue of Viagra

Ups and downs of Viagra: revisiting ototoxicity in the mouse model.

PubMed

Au, Adrian; Stuyt, John Gerka; Chen, Daniel; Alagramam, Kumar

2013-01-01

Sildenafil citrate (Viagra), a phosphodiesterase 5 inhibitor (PDE5i), is a commonly prescribed drug for erectile dysfunction. Since the introduction of Viagra in 1997, several case reports have linked Viagra to sudden sensorineural hearing loss. However, these studies are not well controlled for confounding factors, such as age and noise-induced hearing loss and none of these reports are based on prospective double-blind studies. Further, animal studies report contradictory data. For example, one study (2008) reported hearing loss in rats after long-term and high-dose exposure to sildenafil citrate. The other study (2012) showed vardenafil, another formulation of PDE5i, to be protective against noise-induced hearing loss in mice and rats. Whether or not clinically relevant doses of sildenafil citrate cause hearing loss in normal subjects (animals or humans) is controversial. One possibility is that PDE5i exacerbates age-related susceptibility to hearing loss in adults. Therefore, we tested sildenafil citrate in C57BL/6J, a strain of mice that displays increased susceptibility to age-related hearing loss, and compared the results to those obtained from the FVB/N, a strain of mice with no predisposition to hearing loss. Six-week-old mice were injected with the maximum tolerated dose of sildenafil citrate (10 mg/kg/day) or saline for 30 days. Auditory brainstem responses (ABRs) were recorded pre- and post injection time points to assess hearing loss. Entry of sildenafil citrate in the mouse cochlea was confirmed by qRT-PCR analysis of a downstream target of the cGMP-PKG cascade. ABR data indicated no statistically significant difference in hearing between treated and untreated mice in both backgrounds. Results show that the maximum tolerated dose of sildenafil citrate administered daily for 4 weeks does not affect hearing in the mouse. Our study gives no indication that Viagra will negatively impact hearing and it emphasizes the need to revisit the issue of Viagra

Sildenafil does not improve steady state cardiovascular hemodynamics, peak power, or 15-km time trial cycling performance at simulated moderate or high altitudes in men and women.

PubMed

Kressler, Jochen; Stoutenberg, Mark; Roos, Bernard A; Friedlander, Anne L; Perry, Arlette C; Signorile, Joseph F; Jacobs, Kevin A

2011-12-01

Sildenafil improves oxygen delivery and maximal exercise capacity at very high altitudes (≥ 4,350 m), but it is unknown whether sildenafil improves these variables and longer-duration exercise performance at moderate and high altitudes where competitions are more common. The purpose of this study was to determine the effects of sildenafil on cardiovascular hemodynamics, arterial oxygen saturation (SaO(2)), peak exercise capacity (W (peak)), and 15-km time trial performance in endurance-trained subjects at simulated moderate (MA; ~2,100 m, 16.2% F(I)O(2)) and high (HA; ~3,900 m, 12.8% F(I)O(2)) altitudes. Eleven men and ten women completed two HA W (peak) trials after ingesting placebo or 50 mg sildenafil. Subjects then completed four exercise trials (30 min at 55% of altitude-specific W (peak) + 15-km time trial) at MA and HA after ingesting placebo or 50 mg sildenafil. All trials were performed in randomized, counterbalanced, and double-blind fashion. Sildenafil had little influence on cardiovascular hemodynamics at MA or HA, but did result in higher SaO(2) values (+3%, p < 0.05) compared to placebo during steady state and time trial exercise at HA. W (peak) at HA was 19% lower than SL (p < 0.001) and was not significantly affected by sildenafil. Similarly, the significantly slower time trial performance at MA (28.1 ± 0.5 min, p = 0.016) and HA (30.3 ± 0.6 min, p < 0.001) compared to SL (27.5 ± 0.6 min) was unaffected by sildenafil. We conclude that sildenafil is unlikely to exert beneficial effects at altitudes <4,000 m for a majority of the population.

Effects of Kaempferia parviflora Wall. Ex. Baker and sildenafil citrate on cGMP level, cardiac function, and intracellular Ca2+ regulation in rat hearts.

PubMed

Weerateerangkul, Punate; Palee, Siripong; Chinda, Kroekkiat; Chattipakorn, Siriporn C; Chattipakorn, Nipon

2012-09-01

Although Kaempferia parviflora extract (KPE) and its flavonoids have positive effects on the nitric oxide (NO) signaling pathway, its mechanisms on the heart are still unclear. Because our previous studies demonstrated that KPE decreased defibrillation efficacy in swine similar to that of sildenafil citrate, the phosphodiesterase-5 inhibitor, it is possible that KPE may affect the cardiac NO signaling pathway. In the present study, the effects of KPE and sildenafil citrate on cyclic guanosine monophosphate (cGMP) level, modulation of cardiac function, and Ca transients in ventricular myocytes were investigated. In a rat model, cardiac cGMP level, cardiac function, and Ca transients were measured before and after treatment with KPE and sildenafil citrate. KPE significantly increased the cGMP level and decreased cardiac function and Ca transient. These effects were similar to those found in the sildenafil citrate-treated group. Furthermore, the nonspecific NOS inhibitor could abolish the effects of KPE and sildenafil citrate on Ca transient. KPE has positive effect on NO signaling in the heart, resulting in an increased cGMP level, similar to that of sildenafil citrate. This effect was found to influence the physiology of normal heart via the attenuation of cardiac function and the reduction of Ca transient in ventricular myocytes.

Direct effects of tadalafil on lower urinary tract symptoms versus indirect effects mediated through erectile dysfunction symptom improvement: integrated data analyses from 4 placebo controlled clinical studies.

PubMed

Brock, Gerald B; McVary, Kevin T; Roehrborn, Claus G; Watts, Steven; Ni, Xiao; Viktrup, Lars; Wong, David G; Donatucci, Craig

2014-02-01

Tadalafil has regulatory approval for the treatment of men with signs/symptoms of benign prostatic hyperplasia with and without erectile dysfunction. We assessed whether the effects of treatment with tadalafil for lower urinary tract symptoms/benign prostatic hyperplasia are independent of improvements in erectile dysfunction. Four separate analyses used integrated data from 4 randomized, double-blind, placebo controlled studies in men with lower urinary tract symptoms/benign prostatic hyperplasia with and without erectile dysfunction to test whether total I-PSS (International Prostate Symptom Score) improvement was due to improvement in IIEF-EF (International Index of Erectile Function-Erectile Function domain score). Unidirectional and bidirectional path analysis models determined direct and indirect treatment effects mediated by improvements in lower urinary tract symptoms/benign prostatic hyperplasia and erectile dysfunction symptoms. A total of 1,496 men, of whom 77% had erectile dysfunction, received at least 1 dose of tadalafil 5 mg once daily or placebo. The placebo adjusted treatment effect for men with erectile dysfunction was represented by a mean decrease of -2.3 (p <0.0001) in total I-PSS vs -2.2 (p = 0.0007) for men without erectile dysfunction. The correlation between change from baseline in total I-PSS and IIEF-EF was weak (r(2) = 0.08, p <0.0001). The unidirectional path analysis model suggested that the total treatment effect on total I-PSS score improvement (2.25) was derived from a direct treatment effect of 1.57 (70%, p <0.001) and an indirect treatment effect of 0.67 (30% via IIEF-EF improvement, p <0.001). Bidirectional path analysis showed that total I-PSS improvement was largely attributed to direct (92.5%, p <0.001) vs indirect (7.5%, p = 0.32) treatment effects via IIEF-EF improvement. Regardless of the analytical approach, self-reported erectile dysfunction status did not appreciably influence tadalafil treatment response in men with

Evaluation of the Effects of Sildenafil Citrate (Viagra) on Vertebral Artery Blood Flow in Patients with Vertebro-Basilar Insufficiency

PubMed Central

Berilgen, Sait; Ozdemir, Huseyin; Tekatas, Aslan; Ogur, Erkin

2008-01-01

Objective To investigate the effects of sildenafil citrate (Viagra) on the vertebral artery blood flow of patients with vertebro-basilar insufficiency (VBI) using color duplex sonography (CDS). Materials and Methods The study included 21 patients with VBI (aged 31-76; mean 61.0 ± 10.5 yrs). We administered a 50 mg oral dose of sildenafil citrate to all patients. Next, we measured the peak systolic velocity (Vmax), end diastolic velocity (Vmin), resistive index (RI), pulsatility index (PI), diameter, area, and flow volume (FV) of vertebral arteries using CDS before the administration of sildenafil citrate; 45 minutes after, and 75 minutes after administration. Statistical testing was performed using SPSS for windows version 11.0. The statistical test used to determine the outcome of the analysis was the repeated measures analysis of variance (ANOVA) test. Results Compared to the baseline values, the vertebral artery diameter, area, and FV increased significantly following the administration of sildenafil citrate. The diameter, area and FV increased from 3.39 mm at 45 minutes to 3.64 mm at 75 minutes, 9.43 cm2 to 10.80 cm2 at 45 minutes and 10.81 cm2 at 75 minutes, as well as from 0.07 L/min at baseline to 0.09 L/min at 45 minutes and unchanged at 75 minutes, respectively. Conclusion Sildenafil citrate elicited a significant effect on vertebral artery diameter, area and FVs. PMID:19039262

One year efficacy and safety of oral sildenafil treatment in severe pulmonary hypertension.

PubMed

Samarzija, Miroslav; Zuljević, Ervin; Jakopović, Marko; Sever, Branko; Knezević, Aleksandar; Dumija, Zeljko; Vidjak, Vinko; Samija, Mirko

2009-09-01

Severe pulmonary hypertension is a progressive disease which leads to limitations of functional status and poor survival. We evaluated efficacy and safety of a short (3 months) and a long term (12 months) sildenafil treatment in patients with severe pulmonary hypertension. We treated 12 patients with pulmonary hypertension with oral sildenafil. Patients were followed at three time points, at baseline, and after 3 and 12 months of treatment. Primary end point was improvement in functional exercise capacity assesed by 6-minute walk test, and secondary end points were changes in right ventricle hemodynamics. We found significant improvement in 6-minute walk test distance from 357 +/- 193 m at baseline to 431 +/- 179 m after three months and further improvement to 501 +/- 159 m after 12 months (p < 0.01); decrease in right ventricule pressure from 107 +/- 42 mmHg at baseline to 87 +/- 32 mmHg after 12 months (p < 0.01); and, decrease in right ventricule diameter from 3.2 +/- 1.1 cm to 2.76 +/- 0.86 cm after twelve months (p < 0.01). Drug-related adverse events were mild and transient in our group of patients. Long-term (12 months) sildenafil treatment is effective and safe in our patients with idiopathic and chronic thrombo-embolic pulmonary hypertension.

Self-Esteem, Confidence, and Relationships in Men Treated with Sildenafil Citrate for Erectile Dysfunction

PubMed Central

Althof, Stanley E; O' Leary, Michael P; Cappelleri, Joseph C; Glina, Sidney; King, Rosie; Tseng, Li-Jung; Bowler, Jessica L

2006-01-01

BACKGROUND Men with erectile dysfunction (ED) often have low self-esteem, confidence, and sexual relationship satisfaction. OBJECTIVE We evaluated the impact of sildenafil citrate and its generalizability across cultures on self-esteem, confidence, and sexual relationship satisfaction in men with ED using the Self-Esteem And Relationship (SEAR) questionnaire. DESIGN Pooled analysis of 2 double-blind, placebo-controlled, flexible-dose trials of sildenafil with identical protocols: 1 was conducted in the United States and the other in Mexico, Brazil, Australia, and Japan. PATIENTS Men ≥18 years old with ED. MEASUREMENTS The impact of treatment on psychosocial factors associated with ED was determined by patient responses to the SEAR questionnaire. Erectile function was determined using the International Index of Erectile Function (IIEF) and a global efficacy question. Successful sexual intercourse attempts were derived from event logs of sexual activity. Treatment effect sizes were calculated for all study outcomes. RESULTS Compared with patients who received placebo (n = 274), patients who received sildenafil (n = 279) reported significantly greater improvements (P<.0001) in self-esteem, confidence, sexual relationship satisfaction, and in all sexual function domains of the IIEF. Treatment effect sizes were large (range, 0.7 to 1.2) for all SEAR components, and improvement in psychosocial measures showed moderate to high correlations (range, 0.50 to 0.83, P<.0001) with improvement in erectile function, percentage of successful intercourse attempts, and global efficacy. CONCLUSIONS In men with ED from 5 different nations, sildenafil produced substantial improvements in self-esteem, confidence, and sexual relationship satisfaction. Improvements in these psychosocial factors were observed crossculturally and correlated significantly and tangibly with improvements in erectile function. PMID:16836626

Efficacy and safety of sildenafil in the treatment of severe pulmonary hypertension in patients with hemoglobinopathies.

PubMed

Derchi, Giorgio; Forni, Gian Luca; Formisano, Francesco; Cappellini, Maria Domenica; Galanello, Renzo; D'Ascola, Giandomenico; Bina, Patrizio; Magnano, Carmelo; Lamagna, Martina

2005-04-01

During the last decade new approaches to the treatment of pulmonary arterial hypertension (PH) have increased symptomatic relief and prolonged survival. PH is a common sequel of the hemoglobinopathies, thalassemia and sickle cell anemia, but the use of standard oral treatment options, such as calcium channel blockers, endothelin receptor antagonists, and long-term anticoagulation therapy, is limited because of toxicity and poor effectiveness. Sildenafil citrate is a selective and potent inhibitor of cGMP-specific phosphodiesterase-5 (PDE5) which promotes selective smooth muscle relaxation in lung vasculature and has been utilized successfully in the treatment of PH. The primary objective of this study was to evaluate the efficacy of sildenafil treatment in the control of PH in patients with hemoglobinopathies. In this study patients with hemoglobinopathies (thalassemia intermedia n=4; thalassemia major n=2; sickle thalassemia n=1) suffering from severe PH were treated with sildenafil citrate (50 mg b.i.d.) for periods ranging from 4 to 48 months. A significant decrease in pulmonary pressure and improvement in exercise capacity and functional class were observed in all patients. No significant adverse events were reported. These data, in a small group of patients, indicate that sildenafil citrate is effective in the treatment of PH in hemoglobinopathies that cannot be treated with alternative oral drugs and is well tolerated long-term at a daily dose of 100 mg, though studies including more patients may uncover toxicities and limitations of efficacy.

The use of a single daily dose of tadalafil to treat signs and symptoms of benign prostatic hyperplasia and erectile dysfunction

PubMed Central

Gacci, Mauro; Salvi, Matteo; Sebastianelli, Arcangelo; Vignozzi, Linda; Corona, Giovanni; McVary, Kevin T; Kaplan, Steven A; Maggi, Mario; Carini, Marco; Oelke, Matthias

2013-01-01

A strong and independent association between lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) and erectile dysfunction (ED) has been widely evidenced in several clinical epidemiologic studies. Preclinical animal models have provided a great deal of information on potential common pathogenic mechanisms underlying these two clinical identities. Although the efficacy of the most commonly used treatments for LUTS/BPH is well defined, the negative impact of these treatments on sexual function – in particular, on ED – has triggered the search for new treatment options. In this regard, a new role for phosphodiesterase type 5 inhibitors in the treatment of LUTS/BPH and ED has been claimed. Tadalafil is one of the most extensively investigated phosphodiesterase type 5 inhibitors for this new indication. All evidence reported to date suggests that tadalafil 5 mg once daily is a safe and effective treatment option for both LUTS/BPH and ED. PMID:24400241

Sildenafil decreases rat tracheal hyperresponsiveness to carbachol and changes canonical transient receptor potential gene expression after antigen challenge.

PubMed

Sousa, C T; Brito, T S; Lima, F J B; Siqueira, R J B; Magalhães, P J C; Lima, A A M; Santos, A A; Havt, A

2011-06-01

Inhibition of type-5 phosphodiesterase by sildenafil decreases capacitative Ca2+ entry mediated by transient receptor potential proteins (TRPs) in the pulmonary artery. These families of channels, especially the canonical TRP (TRPC) subfamily, may be involved in the development of bronchial hyperresponsiveness, a hallmark of asthma. In the present study, we evaluated i) the effects of sildenafil on tracheal rings of rats subjected to antigen challenge, ii) whether the extent of TRPC gene expression may be modified by antigen challenge, and iii) whether inhibition of type-5 phosphodiesterase (PDE5) may alter TRPC gene expression after antigen challenge. Sildenafil (0.1 µM to 0.6 mM) fully relaxed carbachol-induced contractions in isolated tracheal rings prepared from naive male Wistar rats (250-300 g) by activating the NO-cGMP-K+ channel pathway. Rats sensitized to antigen by intraperitoneal injections of ovalbumin were subjected to antigen challenge by ovalbumin inhalation, and their tracheal rings were used to study the effects of sildenafil, which more effectively inhibited contractions induced by either carbachol (10 µM) or extracellular Ca2+ restoration after thapsigargin (1 µM) treatment. Antigen challenge increased the expression of the TRPC1 and TRPC4 genes but not the expression of the TRPC5 and TRPC6 genes. Applied before the antigen challenge, sildenafil increased the gene expression, which was evaluated by RT-PCR, of TRPC1 and TRPC6, decreased TRPC5 expression, and was inert against TRPC4. Thus, we conclude that PDE5 inhibition is involved in the development of an airway hyperresponsive phenotype in rats after antigen challenge by altering TRPC gene expression.

Initial results utilizing combination therapy for patients with a suboptimal response to either alprostadil or sildenafil monotherapy.

PubMed

Mydlo, J H; Volpe, M A; Macchia, R J

2000-07-01

Intraurethral alprostadil and oral sildenafil are useful in selected patients. However, there continues to be a significant treatment failure rate. Since their mechanisms of action are different, we wanted to evaluate the effectiveness of combination therapy. Of 214 patients treated for erectile dysfunction (ED), 65 were not fully satisfied with the firmness of their erections via monotherapy. Responses were evaluated using the International Index for Erectile Function (IIEF) questionnaire before and after treatment. Group I consisted of 33 patients who tried maximal dose intraurethral alprostadil monotherapy initially, followed by the maximal dose of sildenafil monotherapy, and were still unsatisfied. Group II consisted of 32 patients who tried the maximal dose sildenafil monotherapy initially, followed by the maximal dose of alprostadil monotherapy, and were also unsatisfied. There 65 patients then underwent combination therapy. 60 out of the 65 patients stated they were satisfied with combination therapy. Questionnaire scores for erectile function were 23.1+/-2.0 (114%) for combination therapy vs. 19.2+/-1.8 (77%) and 15.2+/-1.6 (41%) for sildenafil and alprostadil monotherapies (p<0.05). There were no significant differences in responses between the two groups. The men also reported improvement in intercourse and overall satisfaction. Combination therapy may be an option for motivated patients who have a suboptimal response from monotherapy.

Adsorption and inhibitive properties of sildenafil (Viagra) for zinc in hydrochloric acid solution

NASA Astrophysics Data System (ADS)

Fouda, A. S.; Ibrahim, H.; Atef, M.

Sildenafil (Viagra) was investigated as corrosion inhibitor for Zn in 1 M HCl solution using chemical and electrochemical methods at 25 °C. Electrochemical results showed that this drug is efficient inhibitor for Zn in HCl and the inhibition efficiency (IE) reached to 91% at 300 ppm. The IE increases with the drug concentration and decreases with increasing temperature. The adsorption of this drug on Zn surface follows Langmuir adsorption isotherm. The polarization plots revealed that Sildenafil acts as a mixed-type inhibitor. The thermodynamic parameters of activation and adsorption were calculated and discussed. The surface morphology of the Zn specimens was evaluated using scanning electron microscope (SEM), energy dispersive X-ray (EDX), atomic force microscopy (AFM) and Fourier transform infrared spectroscopy (FTIR) techniques.

A Phase I study to determine the pharmacokinetic profile, safety and tolerability of sildenafil (Revatio®) in cardiac surgery: the REVAKI‐1 study

PubMed Central

Ring, Arne; Morris, Tom; Wozniak, Marcin; Sullo, Nikol; Dott, William; Verheyden, Veerle; Kumar, Tracy; Brunskill, Nigel; Vaja, Rakesh

2016-01-01

Aims Acute kidney injury (AKI) is a common and severe complication of cardiac surgery. There is no effective prevention or treatment. Sildenafil citrate (Revatio®, Pfizer Inc.), a phosphodiesterase type 5 inhibitor, prevents post cardiac surgery AKI in pre‐clinical studies, however its use is contraindicated in patients with symptomatic cardiovascular disease. The aim of this study is to assess the safety and pharmacokinetics of intravenous sildenafil in cardiac surgery patients. Methods We conducted an open label, dose escalation study with six patients per dose level. The six doses were 2.5 mg, 5 mg or 10 mg as a bolus, either alone or followed by an additional 2 h infusion of 2.5 mg sildenafil. Results Thirty‐six patients entered the trial, of which 33 completed it. The mean age was 69.9 years. One patient died during surgery, two others were removed from the trial before dosing (all at dose level 5 mg + 2.5 mg). The pharmacokinetic profile of sildenafil was similar to previously published studies. For a dose of 10 mg administered as a bolus followed by 2.5 mg administered over 2 h the results were AUC∞ 537 ng h ml−1, C max 189.4 ng ml−1 and t 1/2 10.5 h. The drug was well tolerated with no serious adverse events related to drug administration. Higher sildenafil doses stabilized post‐surgery nitric oxide bioavailability. Conclusions Pharmacokinetics of sildenafil during cardiopulmonary bypass were comparable to those of other patient groups. The drug was well tolerated at therapeutic plasma levels. These results support the further evaluation of sildenafil for the prevention of AKI in cardiac surgery. PMID:27779776

Tadalafil once daily improves ejaculatory function, erectile function, and sexual satisfaction in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia and erectile dysfunction: results from a randomized, placebo- and tamsulosin-controlled, 12-week double-blind study.

PubMed

Giuliano, François; Oelke, Matthias; Jungwirth, Andreas; Hatzimouratidis, Konstantinos; Watts, Steven; Cox, David; Viktrup, Lars

2013-03-01

Tadalafil, a long-acting phosphodiesterase type 5 inhibitor, is approved for treating signs and symptoms of benign prostatic hyperplasia (BPH) and erectile dysfunction (ED); tamsulosin, an alpha-blocker, is approved for treating signs and symptoms of BPH. To determine the effects of tadalafil or tamsulosin on sexual function, including ejaculation and orgasm, satisfaction, and erectile function, in sexually active men with ED and lower urinary tract symptoms suggestive of BPH (LUTS/BPH). A randomized, double-blind, placebo-controlled study of tadalafil 5 mg once daily for 12 weeks in men with LUTS/BPH; tamsulosin 0.4 mg once daily was an active control. The International Index of Erectile Function (IIEF) questionnaire was administered at baseline and 4, 8, and 12 weeks. Analysis of orgasm and ejaculation was post hoc based on the IIEF-Orgasmic Function (OF) domain (IIEF-Q9 [ejaculatory frequency] and Q10 [orgasmic frequency]). Other measures included IIEF-Intercourse Satisfaction (IS), Overall Satisfaction (OS), and Erectile Function (EF) domains. Changes from baseline to 12 weeks (or last observation) vs. placebo were analyzed using analysis of covariance. Higher IIEF scores indicate better functioning. Of 511 study participants, 310 (60.7%) had ED and were sexually active. The IIEF-OF increased significantly through 12 weeks with tadalafil vs. placebo (P = 0.048), as did IIEF-Q9 (P = 0.045) but not IIEF-Q10 (P = 0.100). Compared with placebo, IIEF-OF, Q9, and Q10 decreased significantly with tamsulosin (all P < 0.05). The IIEF-IS and OS increased significantly at end point with tadalafil (both P < 0.001); for tamsulosin, change was not significant for IS, while OS decreased significantly (P = 0.009). The IIEF-EF domain increased significantly vs. placebo with tadalafil (P < 0.001) but not tamsulosin (P = 0.699). Tadalafil 5 mg once daily significantly improved ejaculation and orgasm, intercourse and overall satisfaction, and erectile function. Men receiving

Ca2+ -activated K+ channel (KCa) stimulation improves relaxant capacity of PDE5 inhibitors in human penile arteries and recovers the reduced efficacy of PDE5 inhibition in diabetic erectile dysfunction.

PubMed

González-Corrochano, R; La Fuente, Jm; Cuevas, P; Fernández, A; Chen, Mx; Sáenz de Tejada, I; Angulo, J

2013-05-01

We have evaluated the influence of calcium-activated potassium channels (KCa ) activation on cGMP-mediated relaxation in human penile tissues from non-diabetic and diabetic patients, and on the effects of PDE5 inhibitors on erectile responses in control and diabetic rats. Cavernosal tissues were collected from organ donors and from patients with erectile dysfunction (ED). Relaxations of corpus cavernosum strips (HCC) and penile resistance arteries (HPRA) obtained from these specimens were evaluated. Intracavernosal pressure (ICP) increases to cavernosal nerve electrical stimulation were determined in anaesthetized diabetic and non-diabetic rats. Concentration-dependent vasodilation to the PDE5 inhibitor, sildenafil, in HPRA was sensitive to endothelium removal, NO/cGMP pathway inhibition and KCa blockade. Accordingly, activation of KCa with NS-8 (10 μM) significantly potentiated sildenafil-induced relaxations in HPRA (EC50 0.49 ± 0.22 vs. 5.21 ± 0.63 μM). In HCC, sildenafil-induced relaxation was unaffected by KCa blockade or activation. Potentiating effects in HPRA were reproduced with an alternative PDE5 inhibitor (tadalafil) and KCa activator (NS1619) and prevented by removing the endothelium. Large-conductance KCa (BK) and intermediate-conductance KCa (IK) contribute to NS-8-induced effects and were immunodetected in human and rat penile arteries. NS-8 potentiated sildenafil-induced enhancement of erectile responses in rats. Activation of KCa recovered the impaired relaxation to sildenafil in diabetic HPRA while sildenafil completely reversed diabetes-induced ED in rats only when combined with KCa activation. Activation of KCa improves vasodilatory capacity of PDE5 inhibitors in diabetic and non-diabetic HPRA, resulting in the recovery of erectile function in diabetic rats. These results suggest a therapeutic potential for KCa activation in diabetic ED. © 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.

Single dose sublingual testosterone and oral sildenafil vs. a dual route/dual release fixed dose combination tablet: a pharmacokinetic comparison

PubMed Central

van Rooij, Kim; de Leede, Leo; Frijlink, Henderik W.; Koppeschaar, Hans P. F.; Olivier, Berend; Tuiten, Adriaan

2016-01-01

Aim The aim was to compare the pharmacokinetic profiles of two formulations of a combination drug product containing 0.5 mg testosterone and 50 mg sildenafil for female sexual interest/arousal disorder. The prototype (formulation 1) consists of a testosterone solution for sublingual administration and a sildenafil tablet that is administered 2.5 h later. The dual route/dual release fixed dose combination tablet (formulation 2) employs a sublingual and an oral route for systemic uptake. This tablet has an inner core of sildenafil with a polymeric time delay coating and an outer polymeric coating containing testosterone. It was designed to increase dosing practicality and decrease potential temporal non‐adherence through circumventing the relatively complex temporal dosing scheme. Methods Twelve healthy premenopausal subjects received both formulations randomly on separate days. Blood was sampled frequently to determine the pharmacokinetics of free testosterone, total testosterone, dihydrotestosterone, sildenafil and N‐desmethyl‐sildenafil. Results Formulation 2 had a higher maximum concentration (C max) for testosterone, 8.06 ng ml–1 (95% confidence interval [CI] 6.84, 9.28) and higher area under the plasma concentration–time curve (AUC), 7.69 ng ml–1 h (95% CI 6.22, 9.16) than formulation 1, 5.66 ng ml–1 (95% CI 4.63, 6.69) and 5.12 ng ml–1 h (95% CI 4.51, 5.73), respectively. Formulation 2 had a lower C max for sildenafil, 173 ng ml–1 (95% CI 126, 220) and a lower AUC, 476 ng ml–1 h (95% CI 401, 551) than formulation 1, 268 ng ml–1 (95% CI 188, 348) and 577 ng ml–1 h (95% CI 462, 692), respectively. Formulation 2 released sildenafil after 2.75 h (95% CI 2.40, 3.10). Conclusions The dual route/dual release fixed dose combination tablet fulfilled its design criteria and is considered suitable for further clinical testing. What is Already Known about this Subject Female sexual interest/arousal disorder (FSIAD) is a

Safety and Effectiveness of Once-Daily Tadalafil (5 mg) Therapy in Korean Men with Benign Prostatic Hyperplasia/Lower Urinary Tract Symptoms in a Real-World Clinical Setting: Results from a Post-Marketing Surveillance Study.

PubMed

Won, Ji Eon; Chu, Ji Yeon; Choi, Hyunah Caroline; Chen, Yun; Park, Hyun Jun; Dueñas, Héctor José

2018-05-01

The aim of this study was to investigate the safety and effectiveness of tadalafil 5 mg once daily (quaque die [everyday], QD) among Korean men with benign prostatic hyperplasia (BPH)/lower urinary tract symptoms (LUTS) in a real-world clinical setting. This was a single-country, prospective, observational cohort study in which patients newly prescribed tadalafil 5 mg QD for the treatment of BPH/LUTS were followed-up for 12±2 or 24±2 weeks, or to the last treatment, during post-marketing surveillance. Safety was evaluated in terms of the frequency of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). Effectiveness was assessed by changes in the International Prostate Symptom Score (IPSS) from baseline to each endpoint. All patients receiving ≥1 dose of tadalafil 5 mg QD (N=637) were included in the safety population. Two percent of patients (n=13) experienced 15 TEAEs of mild (n=10; 66.7%) or moderate (n=5; 33.3%) severity. No severe TEAEs and no SAEs were reported. Effectiveness evaluations included all patients receiving tadalafil who had both baseline and endpoint observations (12-week, N=265; 24-week, N=44). Compared with baseline, the mean IPSS total score (±standard error) significantly improved by 4.7±0.3 and 6.4±0.7 points at the 12- and 24-week endpoints, respectively (p<0.0001), with significant improvements also observed on the storage, voiding, and quality of life subscores. In total, 69.1% of the patients had a clinically meaningful ≥3-point improvement in the IPSS total score. Tadalafil 5 mg QD was well tolerated and effective in Korean men with BPH/LUTS in a real-world clinical setting. Copyright © 2018 Korean Society for Sexual Medicine and Andrology.

Sildenafil Citrate-Restored eNOS and PDE5 Regulation in Sickle Cell Mouse Penis Prevents Priapism Via Control of Oxidative/Nitrosative Stress

PubMed Central

Hsu, Lewis L.; Berkowitz, Dan E.; Champion, Hunter C.; Burnett, Arthur L.

2013-01-01

Sildenafil citrate revolutionized the practice of sexual medicine upon its federal regulatory agency approval approximately 15 years ago as the prototypical phosphodiesterase type 5 inhibitor indicated for the treatment of male erectile dysfunction. We now provide scientific support for its alternative use in the management of priapism, a clinical disorder of prolonged and uncontrolled penile erection. Sildenafil administered continuously to sickle cell mice, which show a priapism phenotype, reverses oxidative/nitrosative stress effects in the penis, mainly via reversion of uncoupled endothelial nitric oxide synthase to the functional coupled state of the enzyme, which in turn corrects aberrant signaling and function of the nitric oxide/cyclic GMP/protein kinase G/phosphodiesterase type 5 cascade. Priapism tendencies in these mice are reverted partially toward normal neurostimulated erection frequencies and durations after sildenafil treatment in association with normalized cyclic GMP concentration, protein kinase G activity and phosphodiesterase type 5 activity in the penis. Thus, sildenafil exerts pleiotropic effects in the penis that extend to diverse erection disorders. PMID:23844149

Sildenafil citrate-restored eNOS and PDE5 regulation in sickle cell mouse penis prevents priapism via control of oxidative/nitrosative stress.

PubMed

Bivalacqua, Trinity J; Musicki, Biljana; Hsu, Lewis L; Berkowitz, Dan E; Champion, Hunter C; Burnett, Arthur L

2013-01-01

Sildenafil citrate revolutionized the practice of sexual medicine upon its federal regulatory agency approval approximately 15 years ago as the prototypical phosphodiesterase type 5 inhibitor indicated for the treatment of male erectile dysfunction. We now provide scientific support for its alternative use in the management of priapism, a clinical disorder of prolonged and uncontrolled penile erection. Sildenafil administered continuously to sickle cell mice, which show a priapism phenotype, reverses oxidative/nitrosative stress effects in the penis, mainly via reversion of uncoupled endothelial nitric oxide synthase to the functional coupled state of the enzyme, which in turn corrects aberrant signaling and function of the nitric oxide/cyclic GMP/protein kinase G/phosphodiesterase type 5 cascade. Priapism tendencies in these mice are reverted partially toward normal neurostimulated erection frequencies and durations after sildenafil treatment in association with normalized cyclic GMP concentration, protein kinase G activity and phosphodiesterase type 5 activity in the penis. Thus, sildenafil exerts pleiotropic effects in the penis that extend to diverse erection disorders.

Influence of sildenafil and donepezil administration on the serum redox balance in experimentally induced lower limb critical ischemia.

PubMed

Constantinescu, Mihaela Ioana; Constantinescu, Dan Petru; Andercou, Aurel; Mironiuc, Ion Aurel

2013-01-01

Chronic lower limb ischemia (CLLI) leads to endothelial cell dysfunctions and endothelial lesions. The use of substances that release nitric oxide and activate endothelial nitric oxide synthase has proved to be useful in increasing angiogenesis and arteriogenesis under critical ischemia conditions. To investigate the therapeutic effect of Sildenafil and Donepezil with a vasodilating action in experimentally induced CLLI and on serum redox homeostasis. The research was performed in 3 groups of rats (n=10 animals/group) with experimentally induced CLLI: group I - control group; group II - animals treated postoperatively with a therapeutic dose of sildenafil, and group III - animals treated postoperatively with a therapeutic dose of donepezil. Oxidative stress (OS) indicators (malondialdehyde - MDA, protein carbonyls - PC), antioxidant (AO) defense indicators (reduced glutathione - GSH and oxidized glutathione - GSSH), and ceruloplasmin (CP) were determined on days 7, 14, 21 and 30. Statistical processing was performed using the Excel application (Microsoft Office 2007), with the StatsDirect v.2.7.2 software. Changes in OS were evidenced in all groups on account of a decrease in MDA and PC. The greatest OS decrease in all groups was on day 30. AO defence changes were represented by decreased levels of GSH and GSSG in all groups, at the studied moments. Intracellular AO defense in the cytosol, nucleus and mitochondria was similar in all groups, (decreased GSH, GSSG and GSH/GSSG ratio). We found increased extracellular levels of GSH, GSSG, and CP and increased extracellular GSH/GSSG ratio at level compared to values on day 7. 1) The administration of sildenafil (group II) and donepezil (group III) has favorable effects on reducing OS in experimentally induced CLLI. 2) Sildenafil and Donepezil administration stimulates extracellular AO defense on account of CP. 3) Sildenafil and Donepezil administration influences intracellular redox homeostasis on account of the GSH

Impact of penile rehabilitation with low-dose vardenafil on recovery of erectile function in Japanese men following nerve-sparing radical prostatectomy

PubMed Central

Nakano, Yuzo; Miyake, Hideaki; Chiba, Koji; Fujisawa, Masato

2014-01-01

Erectile dysfunction (ED) is a major complication after radical prostatectomy (RP); however, debate continues regarding the efficacy of penile rehabilitation in the recovery of the postoperative erectile function (EF). This study included a total of 103 consecutive sexually active Japanese men with localized prostate cancer undergoing nerve-sparing RP, and analyzed the postoperative EF, focusing on the significance of penile rehabilitation. In this series, 24 and 79 patients underwent bilateral and unilateral nerve-sparing RPs, respectively, and 10 or 20 mg of vardenafil was administered to 35 patients at least once weekly, who agreed to undergo penile rehabilitation. Twelve months after RP, 48 (46.6%) of the 103 patients were judged to have recovered EF sufficient for sexual intercourse without any assistance. The proportion of patients who recovered EF in those undergoing penile rehabilitation (60.0%) was significantly greater than that in those without penile rehabilitation (38.2%). Of several parameters examined, the preoperative International Index of Erectile Function-5 (IIEF-5) score and nerve-sparing procedure were significantly associated with the postoperative EF recovery rates in patients with and without management by penile rehabilitation, respectively. Furthermore, univariate analysis identified the preoperative IIEF-5 score, nerve-sparing procedure and penile rehabilitation as significant predictors of EF recovery, among which the preoperative IIEF-5 score and nerve-sparing procedure appeared to be independently associated with EF recovery. Considering these findings, despite the lack of independent significance, penile rehabilitation with low-dose vardenafil could exert a beneficial effect on EF recovery in Japanese men following nerve-sparing RP. PMID:24994781

Safety and efficacy of silodosin and tadalafil in ease of negotiation of large ureteroscope in the management of ureteral stone: A prosective randomized trial.

PubMed

Bhattar, Rohit; Jain, Vipin; Tomar, Vinay; Yadav, Sher Singh

2017-12-01

To evaluate the safety and efficacy of silodosin and tadalafil in ease of negotiation of large size ureteroscope (8/9.8 Fr) in the management of ureteral stone. Between June 2015 and May 2016, 86 patients presented with ureteral stone of size 6-15 mm were on consent randomly assigned to 1 of 3 outpatient treatment arms: silodosin (Group A), tadalafil (Group B), and placebo (Group C). After two weeks of therapy 67 patients underwent ureteroscopy, and ureteral orifice configuration, ureteroscopic negotiation, ureteral dilatation, operating time, procedural complication and drug related side effects were noted in each group. Ureteral negotiation was significantly better in Groups A (73.9%) and B (69.6%) as compared to Group C (38.1%) (p<0.01). Statistically significant difference was noted in the requirement for dilatation in Group C (71.4%) as compared to Groups A (26.1%) and B (39.1%) (p<0.01). Ureteral orifice was found to be more dilated in Groups A (69.6%) and B (60.9%) as compared to Group C (28.6%). Mean operating time was statistically lower in Groups A (35.2 min) and B (34.91 min) as compared to Group C (41.14 min) (p<0.01). Both silodosin and tadalafil not only relax ureteral smooth muscle but also help in forward propagation of large size ureteroscope (8/9.8 Fr) without any significant risk of adverse events.

Safety and efficacy of silodosin and tadalafil in ease of negotiation of large ureteroscope in the management of ureteral stone: A prosective randomized trial

PubMed Central

Bhattar, Rohit; Jain, Vipin; Tomar, Vinay; Yadav, Sher Singh

2017-01-01

Objective To evaluate the safety and efficacy of silodosin and tadalafil in ease of negotiation of large size ureteroscope (8/9.8 Fr) in the management of ureteral stone. Material and methods Between June 2015 and May 2016, 86 patients presented with ureteral stone of size 6–15 mm were on consent randomly assigned to 1 of 3 outpatient treatment arms: silodosin (Group A), tadalafil (Group B), and placebo (Group C). After two weeks of therapy 67 patients underwent ureteroscopy, and ureteral orifice configuration, ureteroscopic negotiation, ureteral dilatation, operating time, procedural complication and drug related side effects were noted in each group. Results Ureteral negotiation was significantly better in Groups A (73.9%) and B (69.6%) as compared to Group C (38.1%) (p<0.01). Statistically significant difference was noted in the requirement for dilatation in Group C (71.4%) as compared to Groups A (26.1%) and B (39.1%) (p<0.01). Ureteral orifice was found to be more dilated in Groups A (69.6%) and B (60.9%) as compared to Group C (28.6%). Mean operating time was statistically lower in Groups A (35.2 min) and B (34.91 min) as compared to Group C (41.14 min) (p<0.01). Conclusion Both silodosin and tadalafil not only relax ureteral smooth muscle but also help in forward propagation of large size ureteroscope (8/9.8 Fr) without any significant risk of adverse events. PMID:29201512

The efficacy and safety of on-demand Elonza; a generic product of sildenafil in Thai men with erectile dysfunction.

PubMed

Wijitsettakul, Udomsak; Pempongkosol, Sompol

2013-06-01

To evaluate the efficacy and safety of Elonza (generic product of sildenafil) 100 mg, a phosphodiesterase type 5 (PDE5) inhibitor, in Thai men with erectile dysfunction (ED). This prospective, Cohort study was conducted for eight weeks. Two hundred ten male patients, older than 20 years of age with ED were enrolled to receive generic product of sildenafil 100 mg taken as needed. Efficacy is evaluated through the International Index of Erectile Function (IIEF) scores for the five separate response domains, erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction domain. After sildenafil administration, erectile function domain scores were significantly increased from baseline, 5.02 (p < 0.001) and 7.19 (p < 0.001) in one month and two months, respectively. Intercourse satisfaction domain scores and overall satisfaction domain scores were significantly increased from baseline, 3.17 (p < 0.001) and 1.74 (p < 0.001) in two months, respectively. Most treatment emergent adverse events were mild or moderate. The most frequent treatment-emergent adverse events were flushing (13.2%), nasal congestion (9.8%), abnormal vision (4.9%), headache (4.4%), dizziness (2.9%), and dyspepsia (0.5%). Elonza, a generic product of sildenafil, was an effective and well-tolerated treatment for ED in Thai men.

Cavernous antioxidant effect of green tea, epigallocatechin-3-gallate with/without sildenafil citrate intake in aged diabetic rats.

PubMed

Mostafa, T; Sabry, D; Abdelaal, A M; Mostafa, I; Taymour, M

2013-08-01

This study aimed to assess the cavernous antioxidant effect of green tea (GT), epigallocatechin-3-gallate (EGCG) with/without sildenafil citrate intake in aged diabetic rats. One hundred and four aged male white albino rat were divided into controls that received ordinary chow, streptozotocin (STZ)-induced aged diabetic rats, STZ-induced diabetic rats on infused green tea, induced diabetic rats on epigallocatechin-3-gallate and STZ-induced diabetic rats on sildenafil citrate added to EGCG. After 8 weeks, dissected cavernous tissues were assessed for gene expression of eNOS, cavernous malondialdehyde (MDA), glutathione peroxidase (GPx), cyclic guanosine monophosphate (cGMP), and serum testosterone (T). STZ-induced diabetic rats on GT demonstrated significant increase in cavernous eNOS, cGMP, GPx and significant decrease in cavernous MDA compared with diabetic rats. Diabetic rats on EGCG demonstrated significant increase in cavernous eNOS, cGMP, GPx and significant decrease in cavernous MDA compared with diabetic rats or diabetic rats on GT. Diabetic rats on EGCG added to sildenafil showed significant increase in cavernous eNOS, cGMP and significant decrease in cavernous MDA compared with other groups. Serum T demonstrated nonsignificant difference between the investigated groups. It is concluded that GT and EGCG have significant cavernous antioxidant effects that are increased if sildenafil is added. © 2012 Blackwell Verlag GmbH.

LC-ESI-MS/MS analysis of phosphodiesterase-5 inhibitors and their analogues in foods and dietary supplements in Korea.

PubMed

Jeong, Ji Hye; Lee, Ji Hyun; Kim, Hyung Joo; Park, Hyoung Joon; Hwang, In Sun; Han, Kyoung Moon; Yoon, Chang-Yong; Cho, Sooyeul; Kim, Woo Seong

2016-01-01

A number of 188 food and dietary supplement samples were collected from 2009 to the first half of 2013 in Korean online and offline stores. A method to identify phosphodiesterase-5 (PDE-5) inhibitors and their analogues using liquid chromatography-electrospray ionisation-mass spectrometry/mass spectrometry (LC-ESI-MS/MS) was validated. Limit of detection and limit of quantitation of liquid-type and solid-type negative samples ranged from 0.05 to 3.33 ng/mL or ng/g and from 0.15 to 10.00 ng/mL or ng/g, respectively. Recoveries ranged from 83% to 112%. Nineteen PDE-5 inhibitors and their analogues were detected, with tadalafil group compounds being the most frequently observed (53.0%), followed by the sildenafil group (42.5%). Tadalafil concentrations ranged from 0.08 to 138.69 mg/g. Compounds were most frequently detected in capsules (in 40 of 80 adulterated samples). To protect public health and food safety, appropriate monitoring of PDE-5 inhibitors and their analogues in foods and dietary supplements is recommended.

Atorvastatin and sildenafil decrease vascular TGF-β levels and MMP-2 activity and ameliorate arterial remodeling in a model of renovascular hypertension

PubMed Central

Guimarães, Danielle A.; Rizzi, Elen; Ceron, Carla S.; Martins-Oliveira, Alisson; Gerlach, Raquel F.; Shiva, Sruti; Tanus-Santos, Jose E.

2015-01-01

Imbalanced matrix metalloproteinase (MMP)-2 activity and transforming growth factor expression (TGF-β) are involved in vascular remodeling of hypertension. Atorvastatin and sildenafil exert antioxidant and pleiotropic effects that may result in cardiovascular protection. We hypothesized that atorvastatin and sildenafil alone or in association exert antiproliferative effects by down-regulating MMP-2 and TGF-β, thus reducing the vascular hypertrophy induced by two kidney, one clip (2K1C) hypertension. Sham and 2K1C rats were treated with oral atorvastatin 50 mg/kg, sildenafil 45 mg/kg, or both, daily for 8 weeks. Blood pressure was monitored weekly. Morphologic changes in the aortas were studied. TGF-β levels were determined by immunofluorescence. MMP-2 activity and expression were determined by in situ zymography, gel zymography, Western blotting, and immunofluorescence. The effects of both drugs on proliferative responses of aortic smooth muscle cells to PDGF and on on MMP-2 activity in vitro were determined. Atorvastatin, sildenafil, or both drugs exerted antiproliferative effects in vitro. All treatments attenuated 2K1C-induced hypertension and prevented the increases in the aortic cross-sectional area and media/lumen ratio in 2K1C rats. Aortas from 2K1C rats showed higher collagen deposition, TGF-β levels and MMP-2 activity and expression when compared with Sham-operated animals. Treatment with atorvastatin and/or sildenafil was associated with attenuation of 2K1C hypertension-induced increases in these pro-fibrotic factors. However, these drugs had no in vitro effects on hr-MMP-2 activity. Atorvastatin and sildenafil was associated with decreased vascular TGF-β levels and MMP-2 activity in renovascular hypertensive rats, thus ameliorating the vascular remodeling. These novel pleiotropic effects of both drugs may translate into protective effects in patients. PMID:26343345

Comparing the effects of treatment with sildenafil and cognitive-behavioral therapy on treatment of sexual dysfunction in women: a randomized controlled clinical trial

PubMed Central

Omidi, Abdollah; Ahmadvand, Afshin; Najarzadegan, Mohammad Reza; Mehrzad, Fateme

2016-01-01

Background Sexual dysfunction in women is prevalent and common in women after menopause. Many attempts to treat patients with sexual dysfunction by cognitive-behavioral therapy (CBT) methods. But to the best of our knowledge, there has been no study that compared these two methods. Objective The aim of this study was to assess and compare the effects of sildenafil and cognitive-behavioral therapy on treatment of sexual dysfunction in women. Methods In this randomized, controlled, clinical trial, 86 women with arousal and orgasm dysfunction were surveyed. The patients were divided into two groups, i.e., sildenafil and CBT groups. The patients in the sildenafil group were treated by 50 mg of oral sildenafil one hour before intercourse, and the other group had weekly sessions of CBT for eight weeks. Sexual dysfunctions were evaluated by the Female Sexual Function Index (FSFI), a sexual satisfaction questionnaire, and the Enrich marital satisfaction scale. Results The mean age of the participants was 33.14 ± 7.34 years. The mean scores for female sexual function index, sexual satisfaction, and the Enrich marital satisfaction scale were increased in both groups during treatment (p < 0.001). It was found that cognitive-behavioral therapy compared to treatment with sildenafil increased all subscales, except arousal, orgasm, and lubrication. Conclusion Cognitive-behavioral therapy is more effective than treatment with sildenafil for improving female sexual function. Clinical trial registration The trial was registered at the Iranian Registry of Clinical Trials (http://www.irct.ir) with the IRCT ID: IRCT2014070318338N1. Funding The authors received no financial support for the research, authorship, and/or publication of this article. PMID:27382439

Histological, morphometric, protein and gene expression analyses of rat retinas with ischaemia-reperfusion injury model treated with sildenafil citrate.

PubMed

Zanoni, Diogo S; Da Silva, Germana A; Ezra-Elia, Raaya; Carvalho, Márcio; Quitzan, Juliany G; Ofri, Ron; Laus, José L; Laufer-Amorim, Renee

2017-06-01

The aim of this study was to better understand the role of apoptosis in a retinal ischaemia-reperfusion injury model and to determine whether sildenafil citrate treatment can prevent retinal cell apoptosis. Thirty-six rats were divided into a control group (n = 6) and two experimentally induced ischaemia-reperfusion groups (7 and 21 days; n = 15 per group). The induced ischaemia-reperfusion groups were treated with sildenafil for 7 and 21 days (n = 10 per group), and 10 animals were treated with a placebo for the same period (n = 5 per group). Paracentesis of the anterior chamber was performed with a 30-G needle attached to a saline solution (0.9%) bag positioned at a height of 150 cm above the eye for 60 min. Intraocular pressure was measured by rebound tonometer (TonoVet ® ). The eyes were analysed by histology and morphometry, and by immunohistochemistry and qRT-PCR for expression of Caspase-7, Caspase-6, Caspase-9, Tnf-r2, Fas-l, Bcl-2 and Bax. Sildenafil-treated animals showed lower levels of histopathological changes (inflammatory, cellular and tissue) than their placebo-treated counterparts at both 7 and 21 days. The retinal ganglion cell layer (RGC) was preserved in the sildenafil groups (SG), with a cell count closer to control than in the placebo groups (PG). Caspase-7 expression was significantly higher in both treated groups at 7 days compared to controls. Gene expression levels in both treatment groups differed from the controls, but in SG Bax and Caspase-6 expression levels were similar to control animals. These results suggest that the main mechanism of retinal cell death in this model is apoptosis, as there is an increase in pro-apoptotic factors and decrease in the anti-apoptotic ones. Also, sildenafil seems to protect the retinal ganglion cell layer from apoptosis. Cell survival was evident in the histological and morphometric analyses, and sildenafil treatment had a protective effect in the apoptosis pathways, with gene expression

Pharmacokinetic interactions among imatinib, bosentan and sildenafil, and their clinical implications in severe pulmonary arterial hypertension

PubMed Central

Renard, Didier; Bouillon, Thomas; Zhou, Ping; Flesch, Gerard; Quinn, Debbie

2015-01-01

Aims This study characterized the population pharmacokinetics (PK) of imatinib in patients with severe pulmonary arterial hypertension (PAH), investigated drug–drug interactions (DDI) among imatinib, sildenafil and bosentan, and evaluated their clinical implications. Methods Plasma concentrations of imatinib, bosentan and sildenafil were collected in a phase III study and were used to characterize the PK of imatinib in this population. DDIs among the three drugs were quantified using a linear mixed model and log-transformed drug concentrations. Results The population mean estimates of apparent clearance (CL/F) and volume (V/F) were 10.8 l h–1 (95% CI 9.2, 12.4 l h–1) and 267 l (95% CI 208, 326 l), respectively. It was estimated that sildenafil concentrations increased, on average, by 64% (95% CI 32%, 103%) and bosentan concentrations by 51% (95% CI 12%, 104%), in the presence of imatinib. Despite increased concentrations of co-medications, treatment differences between imatinib and placebo for change in 6 min walk distance and pulmonary vascular resistance were relatively constant across the entire concentration range for sildenafil and bosentan. Overall, higher concentrations of imatinib and bosentan were not associated with increasing liver enzymes (serum glutamic oxaloacetic transaminases [SGOT]/serum glutamic-pyruvic transaminase [SGPT]). Conclusions Population PKs of imatinib in patients with severe PAH were found comparable with those of patients with chronic myeloid leukemia. Imatinib was found effective regardless of the co-medications and showed intrinsic efficacy beyond merely elevating the concentrations of the co-medications due to DDIs. There was no evidence of increased risk of liver toxicity upon co-administration with bosentan. PMID:25581063

Salt and cocrystals of sildenafil with dicarboxylic acids: solubility and pharmacokinetic advantage of the glutarate salt.

PubMed

Sanphui, Palash; Tothadi, Srinu; Ganguly, Somnath; Desiraju, Gautam R

2013-12-02

Sildenafil is a drug used to treat erectile dysfunction and pulmonary arterial hypertension. Because of poor aqueous solubility of the drug, the citrate salt, with improved solubility and pharmacokinetics, has been marketed. However, the citrate salt requires an hour to reach its peak plasma concentration. Thus, to improve solubility and bioavailability characteristics, cocrystals and salts of the drug have been prepared by treating aliphatic dicarboxylic acids with sildenafil; the N-methylated piperazine of the drug molecule interacts with the carboxyl group of the acid to form a heterosynthon. Salts are formed with oxalic and fumaric acid; salt monoanions are formed with succinic and glutaric acid. Sildenafil forms cocrystals with longer chain dicarboxylic acids such as adipic, pimelic, suberic, and sebacic acids. Auxiliary stabilization via C-H···O interactions is also present in these cocrystals and salts. Solubility experiments of sildenafil cocrystal/salts were carried out in 0.1N HCl aqueous medium and compared with the solubility of the citrate salt. The glutarate salt and pimelic acid cocrystal dissolve faster than the citrate salt in a two hour dissolution experiment. The glutarate salt exhibits improved solubility (3.2-fold) compared to the citrate salt in water. Solubilities of the binary salts follow an inverse correlation with their melting points, while the solubilities of the cocrystals follow solubilities of the coformer. Pharmacokinetic studies on rats showed that the glutarate salt exhibits doubled plasma AUC values in a single dose within an hour compared to the citrate salt. The high solubility of glutaric acid, in part originating from the strained conformation of the molecule and its high permeability, may be the reason for higher plasma levels of the drug.

A Case of Hepatotoxicity Induced by Adulterated "Tiger King", a Chinese Herbal Medicine Containing Sildenafil.

PubMed

Nissan, Ran; Poperno, Alina; Stein, Gideon Y; Shapira, Barak; Fuchs, Shmuel; Berkovitz, Ronny; Hess, Zipora; Arieli, Mickey

2016-01-01

Detection of Phosphodiesterase Type 5 (PDE-5) inhibitors and their analogues in "100% natural" or "herbal" supplements have been described in numerous reports. However, few reports have been published in relation to actual harm caused by counterfeit erectile dysfunction herbal supplements. We describe a case of a 65-year old male admitted to a tertiary hospital with acute liver toxicity, possibly induced by adulterated "Chinese herbal" supplement "Tiger King" for sexual enhancement. Chemical analysis of the tablets discovered the presence of therapeutic doses of sildenafil with no other herbal components. Other medications were excluded as potential causes of the hepatic impairment. According to the Naranjo adverse drug reaction scale and the Roussel Uclaf Causality Assessment Method (RUCAM) the probability of association of Hepatotoxicity with Sildenafil was "possible" and "probable" respectively (Naranjo score of 4, RUCAM score of 7). Within three days of admission, the patient's clinical status and liver function improved without any specific treatment. His liver function tests normalized 30 days post discharge. Further pharmacovigilance actions should be taken by regulatory authorities and pharmaceutical companies in order to determine the relation between sildenafil and hepatotoxicity. This case emphasizes the importance of raising public awareness on the potential dangers of "Tiger king" in particular, and other counterfeit medications or herbal supplements of unknown origin.

Chronic Administration of Tadalafil Improves the Symptoms of Patients with Amicrobic MAGI: An Open Study

PubMed Central

Condorelli, Rosita A.

2017-01-01

Aim of this study was to evaluate the effects of pharmacological treatment with Tadalafil 5 mg daily on symptoms and quality of sperm parameters in selected patients with amicrobic MAGI (male accessory gland inflammation). 120 patients with amicrobic MAGI (mean age 27.0 ± 6.0 years) with mild-moderate ED (erectile dysfunction) according to IIEF-5 (International Index of Erectile Function 5 Items) scores underwent pharmacological treatment with Tadalafil 5 mg daily for six months. Before and after treatment these patients were evaluated through IIEF-5, semen analysis (according to WHO Criteria, 2010), SI-MAGI (Structured Interview about Male Accessory Gland Inflammation), and ultrasound evaluation. Patients with PVE (prostate-vesciculo-epididymitis) showed a significant increase in the percentage of spermatozoa with total (16.0 ± 8.0 versus 30.0 ± 6.0%) and progressive motility (8.00 ± 10.0 versus 25.0 ± 6.00%). It was a significant reduction of the number of patients with complicated ultrasound forms (30.0 versus 52.0) and a significant increase of the number of patients with uncomplicated ultrasound form (90.0 versus 68.0). Finally, there was a significant reduction in the percentage of patients with alterations of sexual function different from DE, such as premature ejaculation (4.00 versus 8.00%), painful ejaculation (4.00 versus 10.0%), delayed ejaculation (12.50 versus 8.00%), and decreased libido (10.0 versus 25.0%). PMID:28465683

Effect of sildenafil citrate on interleukin-1β-induced nitric oxide synthesis and iNOS expression in SW982 cells

PubMed Central

Kim, Kyung-Ok; Park, Shin-Young; Han, Chang-Woo; Chung, Hyun Kee; Ryu, Dae-Hyun

2008-01-01

The purpose of this study was to identify the effect of sildenafil citrate on IL-1β-induced nitric oxide (NO) synthesis and iNOS expression in human synovial sarcoma SW982 cells. IL-1β stimulated the cells to generate NO in both dose- and time-dependent manners. The IL-1β-induced NO synthesis was inhibited by guanylate cyclase (GC) inhibitor, LY83583. When the cells were treated with 8-bromo-cGMP, a hydrolyzable analog of cGMP, NO synthesis was increased upto 5-fold without IL-1β treatment suggesting that cGMP is an essential component for increasing the NO synthesis. Synoviocytes and chondrocytes contain strong cGMP phosphodiesterase (PDE) activity, which has biochemical features of PDE5. When SW982 cells were pretreated with sildenafil citrate (Viagra), a PDE5 specific inhibitor, sildenafil citrate significantly inhibited IL-1β-induced NO synthesis and iNOS expressions. From this result, we noticed that PDE5 activity is required for IL-1β-induced NO synthesis and iNOS expressions in human synovial sarcoma cells, and sildenafil citrate may be able to suppress an inflammatory reaction of synovium through inhibition of NO synthesis and iNOS expression by cytokines. PMID:18587266

Effect of chronic administration of sildenafil citrate (Viagra) on the histology of the retina and optic nerve of adult male rat.

PubMed

Eltony, Sohair A; Abdelhameed, Sally Y

2017-04-01

Abnormal vision has been reported by 3% of patients treated with sildenafil citrate (Viagra). Although many men use Viagra for an extended period for treatment of erectile dysfunction, the implications of the long term-daily use of it on the retina and optic nerve are unclear. To investigate the effect of chronic daily use of sildenafil citrate in a dose equivalent to men preferred therapeutic dose on the histology of the retina and optic nerve of adult male rat. Eighteen adult male Wistar rats were equally divided into three groups. Group I: control. Group II: treated with sildenafil citrate orally (10mg/kg/day) for 8 weeks. Group III (withdrawal): treated as group II and then left for 4 weeks without treatment. Specimens from the retina and optic nerve were processed for light and electron microscopy. In sildenafil citrate treated group, the retina and optic nerve revealed vacuolations and congested blood capillaries with apoptotic endothelial and pericytic cells, and thickened basal lamina. Caspase-3 (apoptotic marker) and CD31 (endothelial marker) expression increased. Glial cells revealed morphological changes: Müller cells lost their processes, activated microglia, astrocytic clasmatodendrosis, degenerated oligodendrocytes surrounded by disintegrated myelin sheathes of the optic nerve fibers. The retina and optic nerve of the withdrawal group revealed less vacuolations and congestion, and partial recovery of the glial cells. Chronic treatment with sildenafil citrate (Viagra) caused toxic effect on the structure of the retina and optic nerve of the rat. Partial recovery was observed after drug withdrawal. Copyright © 2017 Elsevier Ltd. All rights reserved.

Sildenafil citrate treatment enhances amino acid availability in the conceptus and fetal growth in an ovine model of intrauterine growth restriction.

PubMed

Satterfield, M Carey; Bazer, Fuller W; Spencer, Thomas E; Wu, Guoyao

2010-02-01

Adequate placental blood flow is essential for the optimal delivery of nutrients from mother to fetus for conceptus growth. Restricted fetal development results from pathophysiological and environmental factors that alter utero-placental blood flow, placental function, and, therefore, nutrient availability in the fetus. To test this hypothesis, 0, 75, or 150 mg/d sildenafil citrate (Viagra) was administered subcutaneously from d 28 to 115 of gestation to either nutrient-restricted [50% of NRC requirements) or adequately-fed ewes (100% of NRC requirements). On d 115, maternal, fetal, and placental tissues and fluids were collected. Concentrations of total amino acids and polyamines in uterine venous and arterial sera, amniotic and allantoic fluids, and fetal umbilical venous serum were lower (P < 0.05) in nutrient-restricted ewes than in adequately fed ewes, as were the ratios of total amino acids in fetal umbilical venous serum to uterine arterial serum. Sildenafil citrate dose-dependently increased (P < 0.05) total amino acids and polyamines in amniotic fluid, allantoic fluid, and fetal serum without affecting values in maternal serum. Fetal weight was lower (P < 0.05) in nutrient-restricted ewes on d 115. Sildenafil citrate treatment dose-dependently increased (P < 0.05) fetal weight in both nutrient-restricted and adequately fed ewes. This study supports the hypothesis that long-term sildenafil citrate treatment enhances fetal growth, at least in part, by increasing the availability of amino acids in the conceptus. These findings may lead to the clinical use of sildenafil citrate in human pregnancies suspected to be at risk for intrauterine fetal growth retardation.

Sildenafil reduces signs of oxidative stress in pulmonary arterial hypertension: Evaluation by fatty acid composition, level of hydroxynonenal and heart rate variability

PubMed Central

Semen, Khrystyna; Yelisyeyeva, Olha; Jarocka-Karpowicz, Iwona; Kaminskyy, Danylo; Solovey, Lyubomyr; Skrzydlewska, Elzbieta; Yavorskyi, Ostap

2015-01-01

Pulmonary arterial hypertension (PAH) is a rare multifactorial disease with an unfavorable prognosis. Sildenafil therapy can improve functional capacity and pulmonary hemodynamics in PAH patients. Nowadays, it is increasingly recognized that the effects of sildenafil are pleiotropic and may also involve changes of the pro-/antioxidant balance, lipid peroxidation and autonomic control. In present study we aimed to assess the effects of sildenafil on the fatty acids (FAs) status, level of hydroxynonenal (HNE) and heart rate variability (HRV) in PAH patients. Patients with PAH were characterized by an increase in HNE and changes in the FAs composition with elevation of linoleic, oleic, docosahexanoic acids in phospholipids as well as reduced HRV with sympathetic predominance. Sildenafil therapy improved exercise capacity and pulmonary hemodynamics and reduced NT-proBNP level in PAH. Antioxidant and anti-inflammatory effects of sildenafil were noted from the significant lowering of HNE level and reduction of the phopholipid derived oleic, linoleic, docosahexanoic, docosapentanoic FAs. That was also associated with some improvement of HRV on account of the activation of the neurohumoral regulatory component. Incomplete recovery of the functional metabolic disorders in PAH patients may be assumed from the persistent increase in free FAs, reduced HRV with the sympathetic predominance in the spectral structure after treatment comparing to control group. The possibilities to improve PAH treatment efficacy through mild stimulation of free radical reactions and formation of hormetic reaction in the context of improved NO signaling are discussed. PMID:26654977

A single dose, randomized, open-label, cross-over bioequivalence study of sildenafil citrate tablets in healthy Chinese volunteers
.

PubMed

Li, Dai; Wang, Yu-Lu; Xu, Su-Mei; Li, Dan; Li, Xiao-Min; Pan, Jing; Xu, Ping-Sheng

2017-02-01

The present study was designed to evaluate the bioequivalence of a newly developed sildenafil citrate tablet 50 mg (Jinge^®, Test) and a marketed counterpart (Viagra^®, 100 mg, Reference) in healthy adult male Chinese volunteers. This single-dose, randomized, open-label, four-period, and two-treatment self-crossover study included two parts: fasting and postprandial studies. In each part of the study, the subjects were randomly assigned to receive test or reference products (100 mg sildenafil) in a 1 : 1 ratio, and then received the alternative products, following a 1-week washout period. Plasma sildenafil concentrations were analyzed by liquid chromatography-tandem mass spectrometry. Tolerability was assessed during the entire study period. 32 healthy volunteers (aged 19 - 30) were enrolled in the study; 31 volunteers completed the fasting study, while 32 volunteers completed the postprandial study. The test formulation was bioequivalent to the marketed formulation as the 90% CIs for the ratio of geometric means of C_max (fasting: 98.79 - 119.61%; fed: 94.47 - 119.65%), AUC_last (fasting: 98.70 - 109.71%; fed: 96.39 - 112.89%), and AUC_∞ (fasting: 98.45 - 108.87%; fed: 96.36 - 112.74%) were within equivalence limits (80 - 125%) under both fasting and postprandial conditions. When sildenafil was given with high-fat meals, mean C_max was reduced by 23%, and median tmax ranged from 0.75 to 1.50 hours (p ≤ 0.05). However, both AUC_last and AUC_∞ were comparable between fasting and postprandial conditions. No serious adverse events were found among the subjects. This study confirmed that test and reference sildenafil citrate tablets were bioequivalent under fasting and postprandial conditions.
.

Thermosensitive bioadhesive gels for the vaginal delivery of sildenafil citrate: in vitro characterization and clinical evaluation in women using clomiphene citrate for induction of ovulation.

PubMed

Soliman, Ghareb M; Fetih, Gihan; Abbas, Ahmed M

2017-03-01

The objective of this study is to develop and characterize in situ thermosensitive gels for the vaginal administration of sildenafil as a potential treatment of endometrial thinning occurring as a result of using clomiphene citrate for ovulation induction in women with type II eugonadotrophic anovulation. While sildenafil has shown promising results in the treatment of infertility in women, the lack of vaginal pharmaceutical preparation and the side effects associated with oral sildenafil limit its clinical effectiveness. Sildenafil citrate in situ forming gels were prepared using different grades of Pluronic ® (PF-68 and PF-127). Mucoadhesive polymers as sodium alginate and hydroxyethyl cellulose were added to the gels in different concentrations and the effect on gel properties was studied. The formulations were evaluated in terms of viscosity, gelation temperature (T sol-gel ), mucoadhesion properties, and in vitro drug release characteristics. Selected formulations were evaluated in women with clomiphene citrate failure due to thin endometrium (Clinicaltrial.gov identifier NCT02766725). The T sol-gel decreased with increasing PF-127 concentration and it was modulated by addition of PF-68 to be within the acceptable range of 28-37 °C. Increasing Pluronic® concentration increased gel viscosity and mucoadhesive force but decreased drug release rate. Clinical results showed that the in situ sildenafil vaginal gel significantly increased endometrial thickness and uterine blood flow with no reported side effects. Further, these results were achieved at lower frequency and duration of drug administration. Sildenafil thermosensitive vaginal gels might result in improved potential of pregnancy in anovulatory patients with clomiphene citrate failure due to thin endometrium.

Daily tadalafil for the chronic phase of stuttering priapism: a case report.

PubMed

Massenio, Paolo; D'Altilia, Nicola; Sanguedolce, Francesca; Carrieri, Giuseppe; Cormio, Luigi

2018-05-31

Recurrent (stuttering) ischemic priapism is a challenging clinical condition. Frequent recurrences result in frequent hospital admissions whereas treatment with a shunting procedure often results in erectile dysfunction. A 22-year-old man with stuttering idiopathic priapism developed erectile dysfunction (IIEF-5 score 12) following a Winter's shunt; he was given tadalafil, 5 mg/daily, for 6 months. This treatment resulted in progressive restoration of erectile function in the 6 months following the shunt as well as in preventing recurrence of priapic episodes over a 24-month follow-up. This is the first report in literature of chronic treatment of stuttering priapism with a phosphodiesterase-5 inhibitor being able not only to prevent recurrent priapic episodes but also to restore erectile function following a Winter's shunt.

Preclinical safety evaluation of submicronized sildenafil citrate nebulization solution in small experimental animals.

PubMed

Agrawal, Priyanka; Soni, Sandeep; Mittal, Gaurav; Bhatnagar, Aseem

2015-01-01

Sildenafil citrate (SC) nebulization solution has the potential to treat pulmonary hypertension by delivering high concentration directly to the respiratory system while minimizing systemic drug exposure and associated toxicity. The objective of the present study was to evaluate the potential toxicity of aerosolized SC (inhaled) in Sprague dawley rats for 28 days. The rats were randomly divided into five groups (n = 6). Placebo (normal saline) was inhaled to group I (control). Group II was exposed to therapeutic dose (TD): 20 mg/kg, while group 3 and group 4 were exposed to 3 TD and 6 TD, respectively, till 28 days and toxicokinetic parameters were evaluated in group V. The particle size of the nebulized solution of SC (1%) was measured by using Anderson Cascade Impactor. At the end of experiment, all animals were sacrificed. Endpoints used to evaluate potential toxicity of inhaled sildenafil citrate were clinical observations, body weight, and clinical pathology along with broncho-alveolar lavage (BAL) Fluid investigation. ACI study has shown that more than 70% aerosolized drug particles were in submicron range (0.3-0.5 μm). There was no systemic toxicity or clinically limiting local respiratory toxicity associated with inhalation exposure to SC nebulization solution at 6 TD. No significant changes were observed in the level of different blood and BALF parameters in treated groups in comparison to control. Histopathological examination revealed no abnormal findings in the animals of treated group. The data demonstrate that aerosolized sildenafil citrate is well tolerated in rats and suggest its use in humans.

Sildenafil improves blood perfusion in steroid-induced avascular necrosis of femoral head in rabbits via a protein kinase G-dependent mechanism.

PubMed

Song, Qichun; Ni, Jianlong; Jiang, Hongyuan; Shi, Zhibin

2017-10-01

The aim of the study were to evaluate the effect of sildenafil against avascular necrosis of femoral head (ANFH) in a rabbit model, and to study the role of protein kinase G (PKG) pathway and vascular endothelial growth factor (VEGF) in ANFH. Three weeks after inducing ANFH with methylprednisolone injection, 45 female adult New Zealand white rabbits were divided into three groups and treated as follows: group SI received daily intraperitoneal sildenafil with a dose of 10 mg/kg per day; group SD received daily sildenafil identically to group SI plus auricular vein injection DT3 (a specific PKG inhibitor); group NS received only normal saline. The blood perfusion function in the femoral head was measured by perfusion MRI and ink artery infusion. Bilateral femora heads were examined histopathologically for the presence of osteonecrosis; VEGF of tissue was examined by Western blot analysis; cGMP level and PKG activity were also measured. The incidence of ANFH in SI group was significantly lower than that observed in NS and SD groups (p < 0.05). VEGF in SI group was increased compared to NS group. cGMP level and PKG activity were also significantly different between NS and SI group (p < 0.05). However, these effects of sildenafil in SD group were all markedly inhibited by the administration of DT3 compared to SI group. Sildenafil appear to increase the perfusion of femoral head by up-regulating VEGF through PKG pathway. The increased perfusion of femoral head could prevent ANFH. Copyright © 2017 Turkish Association of Orthopaedics and Traumatology. Production and hosting by Elsevier B.V. All rights reserved.

Comparison of erythropoietin and sildenafil protective role against ischemia/reperfusion injury of the testis in adult rats.

PubMed

Zavras, Nick; Kostakis, Ioannis D; Sakellariou, Stratigoula; Damaskos, Christos; Roupakas, Evangelos; Tsagkari, Eleni; Spartalis, Eleftherios; Velaoras, Konstantinos; Dontas, Ismene A; Karatzas, Theodore

2014-04-01

Tissue damage in testicular torsion/detorsion is caused not only by the ischemia, but also by the ischemia/reperfusion injury after detorsion. Erythropoietin and sildenafil are considered to protect against ischemia/reperfusion injury. Here, we studied and compared their actions in testicular torsion/detorsion in adult rats. Twenty-two adult male Wistar Albino rats were divided into four groups. Rats in group A (n = 5) were sham operated. Rats in group B (n = 5), group C (n = 6) and group D (n = 6) underwent torsion of the right testis and detorsion after 90 min. No pharmaceutical intervention was performed in group B. Erythropoietin (1,000 IU/kg) and sildenafil (0.7 mg/kg) were injected intraperitoneally in groups C and D, respectively, after 60 min of torsion. All animals were killed 24 h after detorsion, and their right testis was extracted, placed into 10 % formalin solution and sent for histopathological examination. The histological changes in the testes were scored according to the four-point grading system proposed by Cosentino et al. All rats in group A had normal testicular architecture (grade 1). The untreated group B had a mean grade of 3.81 (range 3.65-4). The treated groups C (mean grade 3.24; range 3.05-3.45) and D (2.69, range 2.4-2.9) presented statistically significant better results (lower grades) compared with the untreated group B. Group D had significantly better results (lower grades) than group C. The intraperitoneal injection of erythropoietin and sildenafil protects against ischemia/reperfusion injury after testicular torsion and detorsion. Sildenafil may have a stronger action than erythropoietin at the doses used in this study.

Modeling and simulation of sexual activity daily diary data of patients with female sexual arousal disorder treated with sildenafil citrate (Viagra).

PubMed

Claret, Laurent; Cox, Eugene H; McFadyen, Lynn; Pidgen, Alwyn; Johnson, Patrick J; Haughie, Scott; Boolell, Mitra; Bruno, Rene

2006-08-01

To develop a model to explore the dose-response of sildenafil citrate in patients with female sexual arousal disorder (FSAD) based on telephone sexual activity daily diary (TSADD) data obtained in double-blind, placebo controlled clinical studies. Data were available on 614 patients with FSAD. A parametric model (Weibull distribution) was developed to describe the probability density function of the time between sexual events. Orgasm satisfaction scores and overall sexual satisfaction scores were simultaneously modeled as ordered categorical variables. Simulations were performed to evaluate the expected clinical response in patients with FSAD. The expected time between sexual events was approximately 3.5 days. Satisfaction scores increased with time to achieve a plateau after 3 to 4 weeks on treatment. The expected probability of satisfying orgasm (score of 3 and higher) ranged from 34.7% for placebo to 41.6% for 100 mg sildenafil citrate. Treatment effect (difference from placebo) was 6.9% for 100 mg sildenafil citrate, ranging from 0.6 to 24.7% for testosterone levels of 0.1 to 4.0 pg/ml. The treatment effect in postmenopausal women was larger than in premenopausal women. A modeling and simulation framework to support drug development in FSAD was developed. Sildenafil citrate demonstrated a dose-dependent effect in patients with FSAD.

Sildenafil citrate as oral solid lipid nanoparticles: a novel formula with higher bioavailability and sustained action for treatment of erectile dysfunction.

PubMed

Hosny, Khaled M; Aljaeid, Bader M

2014-07-01

The aim of this study was to prepare sildenafil citrate as solid lipid nanoparticles (SLNs), in order to find an innovative way for alleviating the disadvantages associated with commercially available sildenafil citrate tablets. These limitations include poor solubility and extensive first-pass metabolism, resulting in low (40%) bioavailability and short elimination half-life (4 h). SLNs were prepared by hot homogenization followed by ultrasonication. Solubility of sildenafil citrate in different solid lipids was measured, effect of process variables as surfactant type and concentration, homogenization time, ultrasonication time and charge-inducing agent on the particle size, zeta potential and encapsulation efficiency were also determined. Furthermore, in vitro drug release, stability and in vivo pharmacokinetics were studied in rabbits Results: The best SLN formula consisted of 2% precirol ATO5, 0.5% phosphatidylcholine, 2.5% gelucire 44/14, 0.125% stearylamine, had an average particle size of 28.5 nm with 95.34% entrapment efficiency and demonstrated a controlled drug release over 24 h. An in vivo pharmacokinetic study revealed enhanced bioavailability by > 1.87 fold, and the mean residence time was longer than that for the commercially available tablet. SLN could be a promising carrier for sustained/prolonged sildenafil citrate release with enhanced oral bioavailability.

Randomized, Double-Blinded, Placebo-Controlled Crossover Trial of Treating Erectile Dysfunction with Sildenafil After Radiotherapy and Short-Term Androgen Deprivation Therapy: Results of RTOG 0215

PubMed Central

Bruner, Deborah Watkins; James, Jennifer L.; Bryan, Charlene J.; Pisansky, Thomas M.; Rotman, Marvin; Corbett, Thomas; Speight, Joycelyn; Byhardt, Roger; Sandler, Howard; Bentzen, Søren; Kachnic, Lisa; Berk, Lawrence

2013-01-01

Introduction Erectile dysfunction (ED) may be the most commonly observed adverse event (AE) associated with the combination of radiation therapy (RT) and androgen deprivation therapy (ADT). A significant number of men are trying phosphodiesterase type 5 inhibitors (PDE5s) such as sildenafil to treat ED, yet sildenafil studies to date shed little light on the response to ED after ADT. Aim The purpose of this trial was to evaluate sildenafil in the treatment of ED in prostate cancer patients previously treated with external beam RT and neoadjuvant and concurrent ADT. Methods In this randomized, double-blinded crossover trial, eligible patients received RT/ADT for intermediate risk prostate cancer and currently had ED as defined by the International Index of Erectile Function (IIEF). Patients were randomized to 12 weeks of sildenafil or placebo followed by 1 week of no treatment then 12 weeks of the alternative. Treatment differences were evaluated using a marginal model for binary crossover data. Main Outcome Measures The primary end point was improved erectile function, as measured by the IIEF. Results The study accrued 115 patients and 61 (55%) completed all three IIEF assessments. Sildenafil effect was significant (P = 0.009) with a difference in probabilities of erectile response of 0.17 (95% confidence interval: 0.06, 0.29), and 0.21 (0.06, 0.38) for patients receiving ≤120 days of ADT. However, as few as 21% of patients had a treatment-specific response, only improving during sildenafil but not during the placebo phase. Conclusions This is the first controlled trial to suggest a positive sildenafil response for ED treatment in patients previously treated with RT/ADT, however, only a minority of patients responded to treatment. ADT duration may be associated with response and requires further study. The overall low response rate suggests the need for study of additional or preventative strategies for ED after RT/ADT for prostate cancer. PMID:21235716

Acute resolution of pulmonary alveolar infiltrates in 10 dogs with pulmonary hypertension treated with sildenafil citrate: 2005-2014.

PubMed

Kellihan, Heidi B; Waller, Kenneth R; Pinkos, Alyssa; Steinberg, Howard; Bates, Melissa L

2015-09-01

To describe clinical canine patients with naturally occurring pulmonary hypertension and radiographic pulmonary alveolar infiltrates before and after treatment with sildenafil. Ten client-owned dogs. A retrospective analysis of dogs with echocardiographically-determined pulmonary hypertension and pulmonary alveolar infiltrates on thoracic radiographs was performed before (PRE) and after (POST) sildenafil therapy. Clinical scores, pulmonary alveolar infiltrate scores and tricuspid regurgitation gradients were analyzed PRE and POST sildenafil. Pulmonary alveolar infiltrates associated with pulmonary hypertension developed in a diffusely patchy distribution (10/10). Sixty percent of dogs had a suspected diagnosis of interstitial pulmonary fibrosis as the etiology of pulmonary hypertension. Median PRE clinical score was 4 (range: 3-4) compared to POST score of 0 (0-2) (p = 0.005). Median alveolar infiltrate score PRE was 10 (5-12) compared to POST score of 4 (0-6) (p = 0.006). Median tricuspid regurgitation gradient PRE was 83 mmHg (57-196) compared to 55 mmHg POST (33-151) (p = 0.002). A subset of dogs with moderate to severe pulmonary hypertension present with diffuse, patchy alveolar infiltrates consistent with non-cardiogenic pulmonary edema. The typical clinical presentation is acute dyspnea and syncope, often in conjunction with heart murmurs suggestive of valvular insufficiency. This constellation of signs may lead to an initial misdiagnosis of congestive heart failure or pneumonia; however, these dogs clinically and radiographically improve with the initiation of sildenafil. Copyright © 2015 Elsevier B.V. All rights reserved.

Characterization of sildenafil citrate tablets of different sources by near infrared chemical imaging and chemometric tools.

PubMed

Sabin, Guilherme P; Lozano, Valeria A; Rocha, Werickson F C; Romão, Wanderson; Ortiz, Rafael S; Poppi, Ronei J

2013-11-01

The chemical imaging technique by near infrared spectroscopy was applied for characterization of formulations in tablets of sildenafil citrate of six different sources. Five formulations were provided by Brazilian Federal Police and correspond to several trademarks of prohibited marketing and one was an authentic sample of Viagra. In a first step of the study, multivariate curve resolution was properly chosen for the estimation of the distribution map of concentration of the active ingredient in tablets of different sources, where the chemical composition of all excipients constituents was not truly known. In such cases, it is very difficult to establish an appropriate calibration technique, so that only the information of sildenafil is considered independently of the excipients. This determination was possible only by reaching the second-order advantage, where the analyte quantification can be performed in the presence of unknown interferences. In a second step, the normalized histograms of images from active ingredient were grouped according to their similarities by hierarchical cluster analysis. Finally it was possible to recognize the patterns of distribution maps of concentration of sildenafil citrate, distinguishing the true formulation of Viagra. This concept can be used to improve the knowledge of industrial products and processes, as well as, for characterization of counterfeit drugs. Copyright © 2013. Published by Elsevier B.V.

Neuroprotective effects of sildenafil against oxidative stress and memory dysfunction in mice exposed to noise stress.

PubMed

Sikandaner, Hu Erxidan; Park, So Young; Kim, Min Jung; Park, Shi Nae; Yang, Dong Won

2017-02-15

Noise exposure has been well characterized as an environmental stressor, and is known to have auditory and non-auditory effects. Phosphodiesterase 5 (PDE5) inhibitors affect memory and hippocampus plasticity through various signaling cascades which are regulated by cGMP. In this study, we investigated the effects of sildenafil on memory deficiency, neuroprotection and oxidative stress in mice caused by chronic noise exposure. Mice were exposed to noise for 4h every day up to 14days at 110dB SPL of noise level. Sildenafil (15mg/kg) was orally administered 30min before noise exposure for 14days. Behavioral assessments were performed using novel object recognition (NOR) test and radial arm maze (RAM) test. Higher levels of memory dysfunction and oxidative stress were observed in noise alone-induced mice compared to control group. Interestingly, sildenafil administration increased memory performance, decreased oxidative stress, and increased neuroprotection in the hippocampus region of noise alone-induced mice likely through affecting memory related pathways such as cGMP/PKG/CREB and p25/CDK5, and induction of free radical scavengers such as SOD1, SOD2, SOD3, Prdx5, and catalase in the brain of stressed mice. Copyright © 2016. Published by Elsevier B.V.

Internet-ordered viagra (sildenafil citrate) is rarely genuine.

PubMed

Campbell, Neil; Clark, John P; Stecher, Vera J; Goldstein, Irwin

2012-11-01

Counterfeit medication is a growing problem. This study assessed the requirement for prescription, cost, origin, and content of medications sold via the Internet and purporting to be the phosphodiesterase type 5 inhibitor Viagra (sildenafil citrate). Pfizer monitored top search results for the query "buy Viagra" on the two leading Internet search engines in March 2011. Orders were placed from 22 unique Web sites claiming to sell Viagra manufactured by Pfizer. Tablets received were assessed for chemical composition. No Web site examined required a prescription for purchase or a health screening survey; 90% offered illegal "generic Viagra." Cost per tablet ranged from $3.28-$33.00. Shipment origins of purchases were Hong Kong (N = 11), the United States (N = 6), and the United Kingdom (N = 2) as well as Canada, China, and India (N = 1 each). Notably, the four Internet pharmacies claiming to be Canadian did not ship medication from a Canadian address. Of 22 sample tablets examined, 17 (77%) were counterfeit, 4 (18%) were authentic, and 1 (5%) was an illegal generic. Counterfeit tablets were analyzed for sildenafil citrate, the active pharmaceutical ingredient (API) of Viagra, and contents varied between 30% and 50% of the label claim. Counterfeits lacked product information leaflets, including appropriate safety warnings, and genuine Viagra formulations. Internet sites claiming to sell authentic Viagra shipped counterfeit medication 77% of the time; counterfeits usually came from non-U.S. addresses and had 30% to 50% of the labeled API claim. Caution is warranted when purchasing Viagra via the Internet. © 2012 International Society for Sexual Medicine.

Sexual function in hypertensive patients receiving treatment.

PubMed

Reffelmann, Thorsten; Kloner, Robert A

2006-01-01

In many forms of erectile dysfunction (ED), cardiovascular risk factors, in particular arterial hypertension, seem to be extremely common. While causes for ED are related to a broad spectrum of diseases, a generalized vascular process seems to be the underlying mechanism in many patients, which in a large portion of clinical cases involves endothelial dysfunction, ie, inadequate vasodilation in response to endothelium-dependent stimuli, both in the systemic vasculature and the penile arteries. Due to this close association of cardiovascular disease and ED, patients with ED should be evaluated as to whether they may suffer from cardiovascular risk factors including hypertension, cardiovascular disease or silent myocardial ischemia. On the other hand, cardiovascular patients, seeking treatment of ED, must be evaluated in order to decide whether treatment of ED or sexual activity can be recommended without significantly increased cardiac risk. The guideline from the first and second Princeton Consensus Conference may be applied in this context. While consequent treatment of cardiovascular risk factors should be accomplished in these patients, many antihypertensive drugs may worsen sexual function as a drug specific side-effect. Importantly, effective treatment for arterial hypertension should not be discontinued as hypertension itself may contribute to altered sexual functioning; to the contrary, alternative antihypertensive regimes should be administered with individually tailored drug regimes with minimal side-effects on sexual function. When phosphodiesterase-5 inhibitors, such as sildenafil, tadalafil and vardenafil, are prescribed to hypertensive patients on antihypertensive drugs, these combinations of antihypertensive drugs and phosphodiesterase 5 are usually well tolerated, provided there is a baseline blood pressure of at least 90/60 mmHg. However, there are two exceptions: nitric oxide donors and alpha-adrenoceptor blockers. Any drug serving as a nitric

Decision tree analyses of key patient characteristics in Middle Eastern/North African and Latin American men treated with long-acting and short-acting PDE5 inhibitors for erectile dysfunction.

PubMed

Rubio-Aurioles, Eusebio; El-Meliegy, Amr; Abdulwahed, Samer; Henneges, Carsten; Sorsaburu, Sebastian; Gurbuz, Sirel

2015-02-01

Phosphodiesterase type 5 (PDE5) inhibitors have discontinuation rates as high as 60% in men with erectile dysfunction. Treatment satisfaction has been significantly associated with treatment continuation. Understanding key characteristics in terms of treatment preference, relationship, and lifestyle issues could provide direction on how to improve compliance with PDE5 inhibitor treatment globally. The objective was to identify subgroups of interest in the pooled database of two observational studies conducted in Latin America (LA) and Middle East/North Africa (MENA) exploring patient characteristics and prescription of either a long- or short-acting PDE5 inhibitor at baseline. Two identical prospective, non-interventional, observational, studies in MENA (N = 493) and LA (N = 511) treated men with an 'on demand' (pro re nata, PRN) PDE5 inhibitor (sildenafil, tadalafil, vardenafil, or lodenafil) during 6 months. In this post-hoc meta-analysis of two observational studies with equal design, pooled data were analyzed to determine patient characteristics and PDE5 inhibitor prescribed/used most likely to be associated with patient expectations, satisfaction, self-esteem, and patient-partner relationships. Decision tree analyses, with and without weighting, were used to identify and describe key features. In each analysis of patient expectations, patient-partner relationship, and self-esteem, we describe the two major subgroups at baseline for each decision tree. Analyses of patient expectations and sexual self-esteem revealed that patients prescribed long-acting PDE5 inhibitors (59%) highlighted the importance of treatment effect duration, second to partner satisfaction with treatment, while patients prescribed short-acting PDE5 inhibitors (32%) placed less importance on treatment effect duration but considerable importance on treatment effect lasting until intercourse completion. Further insights regarding patients, partner relationship characteristics, and

Sildenafil citrate improves self-esteem, confidence, and relationships in men with erectile dysfunction: Results from an international, multi-center, double-blind, placebo-controlled trial.

PubMed

Althof, Stanley E; O'leary, Michael P; Cappelleri, Joseph C; Hvidsten, Kyle; Stecher, Vera J; Glina, Sidney; King, Rosie; Siegel, Richard L

2006-05-01

Erectile dysfunction (ED) can significantly impact a man's relationships and well-being. We assessed changes in self-esteem, confidence, sexual relationship satisfaction, and overall relationship satisfaction in men with ED using the validated Self-Esteem And Relationship questionnaire (SEAR). This was a 12-week, double-blind, placebo-controlled, flexible-dose (25, 50, 100 mg, as needed) international study of sildenafil in men > or =18 years of age in Mexico, Brazil, Australia, and Japan. The primary study outcome was change in self-esteem from baseline to the end of treatment. Secondary study measures were changes in other SEAR components, International Index of Erectile Function (IIEF) domains, percentage of intercourse attempts that were successful, and the response to a global efficacy question at the end of treatment. Patients were well balanced for age and duration of ED (placebo = 149 and sildenafil = 151). Compared with placebo, sildenafil significantly improved self-esteem, confidence, sexual relationship satisfaction, and overall relationship satisfaction (P < 0.0001). The psychosocial measures of well-being assessed with the SEAR were positively correlated (range 0.60-0.86, P < 0.0001) with erectile function, the frequency of achieving erections that allowed satisfactory sexual intercourse, the percentage of successful sexual intercourse attempts, and global treatment efficacy. Significant improvements in self-esteem, confidence, sexual relationship satisfaction, and overall relationship satisfaction after treatment of ED with sildenafil were consistent among countries. These data suggest a substantial cross-cultural improvement in well-being after successful treatment of ED with sildenafil.

Analysis of single items on the Self-Esteem and Relationship questionnaire in men treated with sildenafil citrate for erectile dysfunction: results of two double-blind, placebo-controlled trials.

PubMed

Cappelleri, Joseph C; Althof, Stanley E; O'Leary, Michael P; Tseng, Li-Jung

2008-04-01

To evaluate the effect of sildenafil citrate on each item of the 14-item Self-Esteem And Relationship (SEAR) questionnaire, which is used to measure self-esteem, confidence, satisfaction with sexual relationship, and overall relationship satisfaction in men with erectile dysfunction (ED). Data were combined from two 12-week, double-blind, placebo-controlled, flexible-dose sildenafil trials having identical protocols, one conducted in the USA and the other in Mexico, Brazil, Australia and Japan. All men had ED and were aged >or=18 years. Response categories of each SEAR item used a 4-week reference period and were based on a five-point scale (1, almost never/never; 2, a few times; 3, sometimes; 4, most times; 5, almost always/always). The difference (sildenafil vs placebo) in the change from baseline to week 12 was evaluated with a Wilcoxon rank sum test using ridit analysis, and an analysis of covariance model that included treatment group, centre, study and baseline item score. Compared with the 274 patients receiving placebo, the 279 receiving sildenafil reported significantly greater mean and median improvements (P < 0.001) in each of the 14 SEAR items. The probability of increased psychosocial benefit from baseline to week 12 was higher with sildenafil for each SEAR item, and ranged from 0.60 ('My partner was unhappy with the quality of our sexual relations'[item reverse-scored]) to 0.72 ('I was satisfied with my sexual performance'). Across all items, the mean (sd) probability was 0.67 (0.04) that a randomly selected patient in the sildenafil group would have a more favourable change relative to a randomly selected patient in the placebo group. Sildenafil produced substantial and meaningful improvements at the item-specific level. This analysis complements previously published work on self-esteem, confidence and relationship satisfaction.

Comparison of the therapeutic effects of sildenafil citrate, heparin and neuropeptides in a rat model of acetic acid-induced gastric ulcer.

PubMed

Kalayci, Mehmet; Kocdor, Mehmet Ali; Kuloglu, Tuncay; Sahin, İbrahim; Sarac, Mehmet; Aksoy, Aziz; Yardim, Meltem; Dalkilic, Semih; Gursu, Onur; Aydin, Suna; Akkoc, Ramazan Fazil; Ugras, Meltem; Artas, Gokhan; Ozercan, İbrahim Hanifi; Ugur, Kader; Aydin, Suleyman

2017-10-01

The purpose of our investigative work has been to determine whether there can be therapeutic roles in the administration of sildenafil citrate, heparin and several neuropeptides on an animal model where gastric ulcers were induced with acetic acid, and to compare their efficacy. The animals were divided into 13 groups, with 4 animals in each. Gastric ulcers was induced in the animals of 12 groups with one untreated group being left as the control (Group I - control; given normal saline (NS)). The other groups were: Group II (ulcer+NS); Group III (5mg/kg sildenafil citrate, low dose); Group IV (10mg/kg sildenafil citrate, high dose); Group V (0.6mg/kg heparin, low dose); Group VI (6mg/kg heparin, high dose); Group VII (20nmol/kg des-acyl ghrelin); Group VIII (40nmol/kg des-acyl ghrelin); Group IX (4nmol/kg acyl ghrelin); Group X (8nmol/kg acly ghrelin); Group XI (20pmol/kg Nesfatin-1); Group XII (15nmol/kg Obestatin) and Group XIII (5nmol/kg Neuropeptide Y). Gastric neuropeptide expression was measured using an immunohistochemical method, and the amount in circulation was detected using ELISA. To compare with no treatment, the controls and other treatment groups, we recorded loss of the surface epithelium of the stomach, erosion, bleeding and inflammatory cell infiltration in the upper halves of the gastric glands. The muscularis and the layers beneath it were, however, apparently normal. The gastric mucosa healed with little or no inflammation when sildenafil citrate, low dose heparin, ghrelin, NUCB2/Nesfatin-1, obestatin, Neuropeptide Y were administered. Overall the data indicate that low dose heparin, and especially sildenafil citrate and neuropeptides, can be used clinically as an alternative approach in the treatment of the gastric ulcer. Copyright © 2017 Elsevier Inc. All rights reserved.

The Immediate Effect of Sildenafil on Right Ventricular Function in Patients with Heart Failure Measured by Cardiac Magnetic Resonance: A Randomized Control Trial

PubMed Central

Durães, André Rodrigues; Borges, Sirlene Mendes; Aras, Roque

2015-01-01

Background Studies have demonstrated that phosphodiesterase 5 (PDE5) inhibition is associated with right ventricle (RV) functional improvement in patients with primary pulmonary hypertension. This study aims to demonstrate the immediate impact of Sildenafil, a PDE5 inhibitor, on RV function, measured by cardiovascular magnetic resonance (CMR), in patients with heart failure (HF). Methods We conducted a randomized double-blind controlled trial. Inclusion criteria: diagnosis of HF functional class I-III; left ventricle ejection fraction < 35%. Patients underwent CMR evaluation and were then equally randomly assigned to either 50 mg of Sildenafil or Placebo groups. One hour following drug administration, they were submitted to a second scan examination. Results 26 patients were recruited from a tertiary reference center in Brazil and 13 were allocated to each study group. The median age was 61.5 years (50–66.5 years). Except for the increase in RV fractional area change following the administration of sildenafil (Sildenafil [before vs. after]: 34.3 [25.2–43.6]% vs. 42.9 [28.5–46.7]%, p = 0.04; Placebo [before vs. after]: 28.1 [9.2–34.8]% vs. 29.2 [22.5–38.8]%, p = 0.86), there was no statistically significant change in parameters. There was no improvement in left ventricular parameters or in the fractional area change of the pulmonary artery. Conclusion This study demonstrated that a single dose of Sildenafil did not significantly improve RV function as measured by the CMR. Trial Registration ClinicalTrials.gov NCT01936350 PMID:25793988

Sildenafil improves erectile hardness in Chinese men with erectile dysfunction: a real-life study analyzed on age stratification.

PubMed

Zhang, Kai; Xu, Ben; Liu, Defeng; Wang, Xiaofeng; Zhu, Jichuan; Deng, Chunhua; Jin, Jie; Jiang, Hui

2014-04-01

To evaluate the clinical efficacy of sildenafil for the improvement of penile erection hardness in erectile dysfunction (ED) patients and to determine the relationship between this improvement in erection hardness and social and psychological functioning. From 2007 to 2008, a total of 4507 men diagnosed with ED were enrolled from 46 centers in China; 4039 of these patients were treated with sildenafil and asked to complete the Erectile Function domain of the International Index of Erectile Function, Erection Hardness Score, and Quality of Erection Questionnaire. The patients were divided into 5 groups on the basis of their age (group A: 20-30 years; group B: 31-40 years; group C: 41-50 years; group D: 51-60 years; and group E: >60 years). A total of 3837 (95.0%) patients completed the entire study. After sildenafil treatment, the vast majority (96.3%) of the men were able to achieve grade 3-4 erection hardness. Patients with a better baseline erection hardness were more able to achieve grade 4 hardness after treatment (P <.001). Comparisons of the Erection Hardness Score improvement before and after treatment between the age-categorized groups also showed that the erection hardness improvement was much greater in men older than 50 years. Sildenafil can help the vast majority of Chinese ED patients achieve grade 3-4 erection hardness. Grade 4 hardness can improve the patients' sexual life to a greater extent than grade 3 hardness. A marked improvement in erection hardness can be achieved in patients older than 50 years. Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.

Uroflowmetric assessment of acute effects of sildenafil on the voiding of men with erectile dysfunction and symptomatic benign prostatic hyperplasia.

PubMed

Guven, Esref O; Balbay, Mevlana D; Mete, Kilciler; Serefoglu, Ege C

2009-01-01

To evaluate the acute effects of sildenafil (50 mg) on the micturation of men with erectile dysfunction (ED) and concomitant benign prostatic hyperplasia (BPH) with lower urinary tract symptoms (LUTS) using uroflowmetric parameters. A total of 68 male patients randomized into two groups (36 treatment, 32 control groups) with International Prostate Symptom Score (IPSS) greater than 7 and International Index of Erectile Dysfunction-erectile function domain score lower than 26 were enrolled in the study. Patients in the treatment group received a single dose of 50 mg of oral sildenafil. Patients in the control group received no treatment. Prevoiding urine volumes determined ultrasonographically and voided urine volumes were also recorded. Statistical comparisons were made with the use of analysis of variance (ANOVA). Mean ages were similar between treatment and control groups (60.4 +/- 9.8 and 58.6 +/- 8.3 years, respectively, P = 0.430). In the treatment group the maximum and average flow rates increased significantly (Q (max) from 15.6 +/- 6.8 cc/s to 19.3 +/- 7.2 cc/s, P < 0.0001; Q (avg) from 7.3 +/- 3.0 cc/s to 9.1 +/- 3.0 cc/s, P < 0.0001) with sildenafil administration, while other parameters studied remained unchanged. Despite the limitations of variations of uroflowmetry, this study showed that sildenafil improves Q (max) and Q (avg) in patients suffering from ED with concomitant BPH-LUTS. Long-term studies are needed to evaluate the effects on IPSS, side effects, and drug interactions.

Tadalafil modulates aromatase activity and androgen receptor expression in a human osteoblastic cell in vitro model.

PubMed

Aversa, A; Fittipaldi, S; Bimonte, V M; Wannenes, F; Papa, V; Francomano, D; Greco, E A; Lenzi, A; Migliaccio, S

2016-02-01

Phosphodiesterase type-5 inhibitor (PDE5i) tadalafil administration in men with erectile dysfunction is associated with increased testosterone/estradiol ratio, leading to hypothesize a potential increased effect of androgen action on target tissues. We aimed to characterize, in a cellular model system in vitro, the potential modulation of aromatase and sex steroid hormone receptors upon exposure to tadalafil (TAD). Human osteoblast-like cells SAOS-2 were chosen as an in vitro model system since osteoblasts are target of steroid hormones. Cells were tested for viability upon TAD exposure, which increased cell proliferation. Then, cells were treated with/without TAD for several times to evaluate potential modulation in PDE5, aromatase (ARO), androgen (AR) and estrogen (ER) receptor expression. Osteoblasts express significant levels of both PDE5 mRNA and protein. Exposure of cells to increasing concentrations of TAD (10(-8)-10(-7) M) decreased PDE5 mRNA and protein expression. Also, TAD inhibited ARO mRNA and protein expression leading to an increase in testosterone levels in the supernatants. Interestingly, TAD increased total AR mRNA and protein expression and decreased ERα, with an increased ratio of AR/ER, suggesting preferential androgenic vs estrogenic pathway activation. Our results demonstrate for the first time that TAD decreases ARO expression and increases AR protein expression in human SAOS-2, strongly suggesting a new control of steroid hormones pathway by PDE5i. These findings might represent the first evidence of translational actions of PDE5i on AR, which leads to hypothesize a growing relevance of this molecule in men with prostate cancer long-term treated with TAD for sexual rehabilitation.

The influence of Sildenafil citrate on uterine tissue perfusion and the cardiovascular system during the luteal phase of the ovarian cycle in cows.

PubMed

Dzięcioł, Michał; Stańczyk, Ewa; Noszczyk-Nowak, Agnieszka; Michlik, Katarzyna; Kozdrowski, Roland; Niżański, Wojciech; Pasławskab, Urszula; Mrowiec, Jacek; Twardoń, Jan

2014-03-01

The aim of the study was to evaluate the influence of the Sildenafil citrate on the blood flow in the uterus of cows during dioestrus. Uterine blood flow was examined in five, healthy, adult cows. Between day 6-8 of the ovarian cycle, each cow received 200mg of sildenafil diluted in 10ml of warm saline into the body of the uterus. Analysis of the blood pressure, ECG and the maximum velocity in m/s (V max) in the aorta was performed and selected parameters of the blood flow (PI, pulsatile index; RI, resistance index; SPV, systolic peak velocity; EDV, end diastolic velocity; FVI, flow velocity integral; SV/DV, systolic peak velocity: end-diastolic velocity ratio) were measured in the uterine artery (Arteria uterine) before and after sildenafil infusion. In addition, Color Doppler examination of the uterine wall perfusion was analyzed. A significant decrease of values of PI and SV/DV ratio as well as an increase of end diastolic velocity and time averaged maximum velocity was noted. With the use of color coded sonography, the increased intensity of the blood flow in the uterine wall was observed. It was concluded that intrauterine administration of sildenafil during dioestrus can increase uterine tissue perfusion. Copyright © 2013 Elsevier GmbH. All rights reserved.

Results from different patient populations using combined therapy with alprostadil and sildenafil: predictors of satisfaction.

PubMed

Mydlo, J H; Volpe, M A; MacChia, R J

2000-09-01

To evaluate the outcome of combined therapy (using intraurethral alprostadil and oral sildenafil) in private and clinic patients with erectile dysfunction, and thus assess predictors of satisfaction. In all, 360 men were treated for erectile dysfunction using single and/or combined therapy, comprising 214 private-practice and 166 clinic patients. Responses were evaluated using the International Index for Erectile Function (IIEF) questionnaire before and after treatment. Serum testosterone levels, education and socio-economic status were also assessed. Group 1a consisted of 33 private patients and Group 1b of 24 clinic patients who tried the maximum dose of intraurethral alprostadil monotherapy initially, followed by the maximum dose of sildenafil monotherapy, and remained dissatisfied. Group 2a consisted of 32 private patients and group 2b of 31 clinic patients who tried the maximum dose of sildenafil monotherapy initially, followed by the maximum dose of alprostadil monotherapy, and were also dissatisfied. These two groups of 65 private and 55 clinic patients then underwent combined therapy. The mean (SD) score for erectile function was 24.1 (2) for combined therapy (a 123% improvement), and 19.8 (1. 8) (83% improvement) and 15.2 (1.6) (41% improvement) for sildenafil and alprostadil monotherapies (P < 0.05 for both patient groups). The men also reported an improvement in their satisfaction with intercourse. However, at 18 months, 60 of the 65 private patients but only 40 of the 55 clinic patients continued with combined therapy; thus, the discontinuation rate was three times greater among clinic than among private patients. Furthermore, the private patients had an overall improvement in the satisfaction score of 128%, compared with 51% for the clinic patients. Although there were no significant differences in erectile function improvement within the two satisfied combined therapy groups, the differences in overall satisfaction and long-term withdrawal rates

Phosphodiesterase Type 5 Inhibitors for the Treatment of Erectile Dysfunction: Pharmacology and Clinical Impact of the Sildenafil Citrate Orodispersible Tablet Formulation.

PubMed

Scaglione, Francesco; Donde, Shaantanu; Hassan, Tarek A; Jannini, Emmanuele A

2017-02-01

The purpose of this review is to provide an overview of the pharmacology, tolerability, and efficacy of the different phosphodiesterase type 5 (PDE5) inhibitors available for the treatment of erectile dysfunction (ED), with a special focus on the sildenafil orodispersible tablet (ODT) formulation. A literature search was performed in PubMed, EMBASE, and Cochrane Reviews using the terms erectile dysfunction, patient preference, sildenafil, and PDE5 inhibitors to identify articles published in English between May 1, 2006, and November 18, 2016. A total of 29 studies were included in this review. There are substantial data in the literature on the use of PDE5 inhibitors for the treatment of ED. Oral PDE5 inhibitors have been found to be efficacious in the treatment of ED based on results from standard tools used to assess treatment outcomes, such as the Global Assessment Questionnaire 1. In addition, PDE5 inhibitors are defined as well tolerated because of the low occurrence of serious adverse effects or discomfort. Mild adverse reactions, compared with a placebo, include headache, flushing, dyspepsia, abnormal vision, nasal congestion, back pain, myalgia, nausea, dizziness, and rash. Both the film-coated tablet and ODT formulations of sildenafil with or without water have equivalent systemic exposure. However, use of a sildenafil ODT formulation offers a convenient alternative method of administration that would be advantageous for patients with ED. According to the published literature, the PDE5 inhibitors are considered an effective and well-tolerated option for the treatment of ED as determined by data generated from standard instruments used in the assessment of treatment outcomes in ED and reported types and severity of adverse effects. The sildenafil ODT formulation, which disintegrates rapidly in the mouth, is an alternative to the solid film-coated tablet formulation that offers administration benefit with the potential to improve treatment adherence, thereby

Maternal Administration of Sildenafil Citrate Alters Fetal and Placental Growth and Fetal-Placental Vascular Resistance in the Growth-Restricted Ovine Fetus.

PubMed

Oyston, Charlotte; Stanley, Joanna L; Oliver, Mark H; Bloomfield, Frank H; Baker, Philip N

2016-09-01

Intrauterine growth restriction (IUGR) causes short- and long-term morbidity. Reduced placental perfusion is an important pathogenic component of IUGR; substances that enhance vasodilation in the uterine circulation, such as sildenafil citrate (sildenafil), may improve placental blood flow and fetal growth. This study aimed to examine the effects of sildenafil in the growth-restricted ovine fetus. Ewes carrying singleton pregnancies underwent insertion of vascular catheters, and then, they were randomized to receive uterine artery embolization (IUGR) or to a control group. Ewes in the IUGR group received a daily infusion of sildenafil (IUGR+SC; n=10) or vehicle (IUGR+V; n=8) for 21 days. The control group received no treatment (n=9). Umbilical artery blood flow was measured using Doppler ultrasound and the resistive index (RI) calculated. Fetal weight, biometry, and placental weight were obtained at postmortem after treatment completion. Umbilical artery RI in IUGR+V fell less than in controls; the RI of IUGR+SC was intermediate to that of the other 2 groups (mean±SEM for control versus IUGR+V versus IUGR+SC: ∆RI, 0.09±0.03 versus -0.01±0.02 versus 0.03±0.02; F(2, 22)=4.21; P=0.03). Compared with controls, lamb and placental weights were reduced in IUGR+V but not in IUGR+SC (control versus IUGR+V versus IUGR+SC: fetal weight, 4381±247 versus 3447±235 versus 3687±129 g; F(2, 24)=5.49; P=0.01 and placental weight: 559.7±35.0 versus 376.2±32.5 versus 475.2±42.5 g; F(2, 24)=4.64; P=0.01). Sildenafil may be a useful adjunct in the management of IUGR. An increase in placental weight and fall in fetal-placental resistance suggests that changes to growth are at least partly mediated by changes to placental growth rather than alterations in placental efficiency. © 2016 American Heart Association, Inc.

Safety and efficacy of sildenafil citrate in treating erectile dysfunction in patients with combat-related post-traumatic stress disorder: a double-blind, randomized and placebo-controlled study.

PubMed

Safarinejad, Mohammad Reza; Kolahi, Ali Asgar; Ghaedi, Gholamhossein

2009-08-01

To evaluate the safety and efficacy of sildenafil citrate for treating erectile dysfunction (ED) in patients with combat-related post-traumatic stress disorder (PTSD). In all, 266 combat-exposed war veterans with ED (aged 37-59 years) were recruited. They met the Diagnostic and Statistical Manual of Mental Disorders-IV criteria for PTSD according to the Structured Clinical Interview for Patients, Investigator Version. The patients were also evaluated with the Clinician-Administered PTSD Scale, both to establish the diagnosis of PTSD and to measure symptom severity. Only patients with psychogenic ED were included in the study. Patients with comorbid conditions (diabetes mellitus, hypercholesterolaemia, hypertension, Peyronie's disease) and smokers of more than five cigarettes daily were excluded. The patients were randomly divided into a group of 133 who received 100 mg of on-demand sildenafil 0.75-2 h before sexual stimulation, and 133 who received placebo. Patients were asked to use > or =16 doses or attempts at home. The efficacy of the treatments was assessed every four attempts during treatment, and at the end of the study, using responses to the 15-question International Index of Erectile Function (IIEF), Sexual Encounter Profile diary questions 2 and 3, Erectile Dysfunction Inventory of Treatment Satisfaction questionnaire, patients' event logs of sexual activity, and a Global Assessment Question about erections. Sildenafil did not produce significantly and substantially greater improvement than placebo in each of the primary and secondary outcome measures (P = 0.08). A normal EF domain score (> or =26) at endpoint was reported by 13 (9.8%), and 11 (8.3%) of patients on the sildenafil and placebo regimens, respectively (P = 0.09). Patients treated with sildenafil had no statistically significantly greater improvement in the five sexual function domains of the IIEF questionnaire than those treated with placebo (P = 0.08). The incidences of treatment

Evaluation of Pharmacokinetic Interactions Between Lesinurad, a New Selective Urate Reabsorption Inhibitor, and CYP Enzyme Substrates Sildenafil, Amlodipine, Tolbutamide, and Repaglinide.

PubMed

Gillen, Michael; Yang, Chun; Wilson, David; Valdez, Shakti; Lee, Caroline; Kerr, Bradley; Shen, Zancong

2017-07-01

Lesinurad is a selective uric acid reabsorption inhibitor approved for the treatment of hyperuricemia associated with gout in combination with xanthine oxidase inhibitors. In vitro assays indicate that lesinurad is an inducer of CYPs in the order CYP3A > CYP2C8 > CYP2C9 > CYP2C19 > CYP2B6 and an inhibitor of CYP2C8 and CYP2C9. To investigate the drug interaction potential of lesinurad, clinical drug interaction studies were conducted. Open-label studies in volunteers investigated the effects of single-/multiple-dose lesinurad on the pharmacokinetics of sildenafil and amlodipine (CYP3A4 induction), tolbutamide (CYP2C9 inhibition/induction), and repaglinide (CYP2C8 inhibition/induction). There was no apparent induction of CYP2C8 and CYP2C9 following repeated lesinurad administration, although no inhibition of CYP2C9 and modest inhibition of CYP2C8 were observed following single-dose lesinurad. Consistent with in vitro observations, lesinurad (200 mg once daily) was an inducer of CYP3A based on the effects on sildenafil exposure. Sildenafil exposure decreased by approximately 34% for C max and AUC when administered with multiple-dose lesinurad 200 mg and allopurinol 300 mg, relative to sildenafil alone. During lesinurad therapy, the possibility of reduced efficacy of concomitant drugs that are CYP3A substrates should be considered and their efficacy monitored because of induction of CYP3A by lesinurad. © 2017, The American College of Clinical Pharmacology.

Preparation, characterization and optimization of sildenafil citrate loaded PLGA nanoparticles by statistical factorial design

PubMed Central

2013-01-01

Background and the aim of the study The objective of the present study was to formulate and optimize nanoparticles (NPs) of sildenafil-loaded poly (lactic-co-glycolic acid) (PLGA) by double emulsion solvent evaporation (DESE) method. The relationship between design factors and experimental data was evaluated using response surface methodology. Method A Box-Behnken design was made considering the mass ratio of drug to polymer (D/P), the volumetric proportion of the water to oil phase (W/O) and the concentration of polyvinyl alcohol (PVA) as the independent agents. PLGA-NPs were successfully prepared and the size (nm), entrapment efficiency (EE), drug loading (DL) and cumulative release of drug from NPs post 1 and 8 hrs were assessed as the responses. Results The NPs were prepared in a spherical shape and the sizes range of 240 to 316 nm. The polydispersity index of size was lower than 0.5 and the EE (%) and DL (%) varied between 14-62% and 2-6%, respectively. The optimized formulation with a desirability factor of 0.9 was selected and characterized. This formulation demonstrated the particle size of 270 nm, EE of 55%, DL of 3.9% and cumulative drug release of 79% after 12 hrs. In vitro release studies showed a burst release at the initial stage followed by a sustained release of sildenafil from NPs up to 12 hrs. The release kinetic of the optimized formulation was fitted to Higuchi model. Conclusions Sildenafil citrate NPs with small particle size, lipophilic feature, high entrapment efficiency and good loading capacity is produced by this method. Characterization of optimum formulation, provided by an evaluation of experimental data, showed no significant difference between calculated and measured data. PMID:24355133

Erythropoietin and sildenafil protect against ischemia/reperfusion injury following testicular torsion in adult rats.

PubMed

Kostakis, Ioannis D; Zavras, Nick; Damaskos, Christos; Sakellariou, Stratigoula; Korkolopoulou, Penelope; Misiakos, Evangelos P; Tsaparas, Petros; Vaos, George; Karatzas, Theodoros

2017-06-01

Testicular torsion/detorsion causes severe tissue damage due to ischemia/reperfusion injury. The present study investigated the protective effect of erythropoietin and sildenafil against ischemia/reperfusion injury following unilateral testicular torsion/detorsion in adult rats. A total of 28 adult male rats were included, and were divided into the following groups: Group A (n=5), sham operated; groups B (n=5), C (n=5), D (n=5) and E (n=8), undergoing right testis torsion and detorsion after 90 min. Group B received no drug treatment. Rats in the groups C and D received low-dose (1,000 IU/kg) or high-dose (3,000 IU/kg) erythropoietin, while those in group E received sildenafil (0.7 mg/kg), through intraperitoneal injection after 60 min of torsion. The right testis was extracted 24 h after detorsion, and the tissue was subjected to histopathological examination and immunohistochemical assessment of cleaved caspase-3 expression. Histological alterations and the quality of spermatogenesis were scored according to the Cosentino and the Johnsen scoring systems, respectively. The results demonstrated normal testicular architecture in group A, while the other groups showed ischemic cellular damages, with the worst scores observed in group B. Groups D and E presented better scores compared with group C. Regarding the quality of spermatogenesis, the best scores were observed in group A, and the worst in group B. Groups C, D and E presented similar results, which were improved in comparison to group B, however, not compared to group A. Furthermore, cleaved caspase-3 levels were lower in groups A, D and E, with equal results observed. Group C had higher levels of cleaved caspase-3 compared with these groups, but lower than group B, which presented the highest cleaved caspase-3 levels. In conclusion, erythropoietin and sildenafil protect testis from ischemia/reperfusion injury by decreasing cellular damage and attenuating apoptosis.

Erythropoietin and sildenafil protect against ischemia/reperfusion injury following testicular torsion in adult rats

PubMed Central

Kostakis, Ioannis D.; Zavras, Nick; Damaskos, Christos; Sakellariou, Stratigoula; Korkolopoulou, Penelope; Misiakos, Evangelos P.; Tsaparas, Petros; Vaos, George; Karatzas, Theodoros

2017-01-01

Testicular torsion/detorsion causes severe tissue damage due to ischemia/reperfusion injury. The present study investigated the protective effect of erythropoietin and sildenafil against ischemia/reperfusion injury following unilateral testicular torsion/detorsion in adult rats. A total of 28 adult male rats were included, and were divided into the following groups: Group A (n=5), sham operated; groups B (n=5), C (n=5), D (n=5) and E (n=8), undergoing right testis torsion and detorsion after 90 min. Group B received no drug treatment. Rats in the groups C and D received low-dose (1,000 IU/kg) or high-dose (3,000 IU/kg) erythropoietin, while those in group E received sildenafil (0.7 mg/kg), through intraperitoneal injection after 60 min of torsion. The right testis was extracted 24 h after detorsion, and the tissue was subjected to histopathological examination and immunohistochemical assessment of cleaved caspase-3 expression. Histological alterations and the quality of spermatogenesis were scored according to the Cosentino and the Johnsen scoring systems, respectively. The results demonstrated normal testicular architecture in group A, while the other groups showed ischemic cellular damages, with the worst scores observed in group B. Groups D and E presented better scores compared with group C. Regarding the quality of spermatogenesis, the best scores were observed in group A, and the worst in group B. Groups C, D and E presented similar results, which were improved in comparison to group B, however, not compared to group A. Furthermore, cleaved caspase-3 levels were lower in groups A, D and E, with equal results observed. Group C had higher levels of cleaved caspase-3 compared with these groups, but lower than group B, which presented the highest cleaved caspase-3 levels. In conclusion, erythropoietin and sildenafil protect testis from ischemia/reperfusion injury by decreasing cellular damage and attenuating apoptosis. PMID:28587411

Effects of Sildenafil Citrate and Heparin Treatments on Placental Cell Morphology in a Murine Model of Pregnancy Loss.

PubMed

Luna, Rayana Leal; Vasconcelos, Anne Gabrielle; Nunes, Ana Karolina Santana; de Oliveira, Wilma Helena; Barbosa, Karla Patricia de Sousa; Peixoto, Christina Alves

2016-01-01

Lipopolysaccharide (LPS) injections during pregnancy are well established as models for pregnancy complications, including fetal growth restriction (FGR), thrombophilia, preterm labor and abortion. Indeed, inflammation, as induced by LPS injection has been described as a pivotal factor in cases of miscarriage related to placental tissue damage. The phosphodiesterase-5 inhibitor sildenafil (Viagra®) is currently used to treat FGR cases in women, while low-molecular weight heparin (Fragmin®) is a standard treatment for recurrent miscarriage (RM). However, the pathways and cellular dynamics involved in RM are not completely understood. The aim of this study was to evaluate the protective effect of sildenafil and dalteparin in a mouse model of LPS-induced abortion. Histopathology, ultrastructural analysis and immunofluorescence for P-selectin were studied in two different placental cell types: trophoblast cells and labyrinth endothelial cells. Treatment with sildenafil either alone or in combination with heparin showed the best response against LPS-induced injury during pregnancy. In conclusion, our results support the use of these drugs as future therapeutic agents that may protect the placenta against inflammatory injury in RM events. Analyses of the ultrastructure and placental immunophysiology are important to understand the mechanism underlying RM. These findings may spark future studies and aid in the development of new therapies in cases of RM. © 2016 S. Karger AG, Basel.

Exploratory Decision-Tree Modeling of Data from the Randomized REACTT Trial of Tadalafil Versus Placebo to Predict Recovery of Erectile Function After Bilateral Nerve-Sparing Radical Prostatectomy.

PubMed

Montorsi, Francesco; Oelke, Matthias; Henneges, Carsten; Brock, Gerald; Salonia, Andrea; d'Anzeo, Gianluca; Rossi, Andrea; Mulhall, John P; Büttner, Hartwig

2016-09-01

Understanding predictors for the recovery of erectile function (EF) after nerve-sparing radical prostatectomy (nsRP) might help clinicians and patients in preoperative counseling and expectation management of EF rehabilitation strategies. To describe the effect of potential predictors on EF recovery after nsRP by post hoc decision-tree modeling of data from A Study of Tadalafil After Radical Prostatectomy (REACTT). Randomized double-blind double-dummy placebo-controlled trial in 423 men aged <68 yr with adenocarcinoma of the prostate (Gleason ≤7, normal preoperative EF) who underwent nsRP at 50 centers from nine European countries and Canada. Postsurgery 1:1:1 randomization to 9-mo double-blind treatment with tadalafil 5mg once a day (OaD), tadalafil 20mg on demand, or placebo, followed by a 6-wk drug-free-washout, and a 3-mo open-label tadalafil OaD treatment. Three decision-tree models, using the International Index of Erectile Function-Erectile Function (IIEF-EF) domain score at the end of double-blind treatment, washout, and open-label treatment as response variable. Each model evaluated the association between potential predictors: presurgery IIEF domain and IIEF single-item scores, surgical approach, nerve-sparing score (NSS), and postsurgery randomized treatment group. The first decision-tree model (n=422, intention-to-treat population) identified high presurgery sexual desire (IIEF item 12: ≥3.5 and <3.5) as the key predictor for IIEF-EF at the end of double-blind treatment (mean IIEF-EF: 14.9 and 11.1), followed by high confidence to get and maintain an erection (IIEF item 15: ≥3.5 and <3.5; IIEF-EF: 15.4 and 7.1). For patients meeting these criteria, additional non-IIEF-related predictors included robot-assisted laparoscopic surgery (yes or no; IIEF-EF: 19.3 and 12.6), quality of nerve sparing (NSS: <2.5 and ≥2.5; IIEF-EF: 14.3 and 10.5), and treatment with tadalafil OaD (yes and no; IIEF-EF: 17.6 and 14.3). Additional analyses after washout and

Exploratory Decision-Tree Modeling of Data from the Randomized REACTT Trial of Tadalafil Versus Placebo to Predict Recovery of Erectile Function After Bilateral Nerve-Sparing Radical Prostatectomy

PubMed Central

Montorsi, Francesco; Oelke, Matthias; Henneges, Carsten; Brock, Gerald; Salonia, Andrea; d’Anzeo, Gianluca; Rossi, Andrea; Mulhall, John P.; Büttner, Hartwig

2017-01-01

Background Understanding predictors for the recovery of erectile function (EF) after nerve-sparing radical prostatectomy (nsRP) might help clinicians and patients in preoperative counseling and expectation management of EF rehabilitation strategies. Objective To describe the effect of potential predictors on EF recovery after nsRP by post hoc decision-tree modeling of data from A Study of Tadalafil After Radical Prostatectomy (REACTT). Design, setting, and participants Randomized double-blind double-dummy placebo-controlled trial in 423 men aged <68 yr with adenocarcinoma of the prostate (Gleason ≤7, normal preoperative EF) who underwent nsRP at 50 centers from nine European countries and Canada. Intervention Postsurgery 1:1:1 randomization to 9-mo double-blind treatment with tadalafil 5 mg once a day (OaD), tadalafil 20 mg on demand, or placebo, followed by a 6-wk drug-free-washout, and a 3-mo open-label tadalafil OaD treatment. Outcome measurements and statistical analysis Three decision-tree models, using the International Index of Erectile Function-Erectile Function (IIEF-EF) domain score at the end of double-blind treatment, washout, and open-label treatment as response variable. Each model evaluated the association between potential predictors: presurgery IIEF domain and IIEF single-item scores, surgical approach, nerve-sparing score (NSS), and postsurgery randomized treatment group. Results and limitations The first decision-tree model (n = 422, intention-to-treat population) identified high presurgery sexual desire (IIEF item 12: ≥3.5 and <3.5) as the key predictor for IIEF-EF at the end of double-blind treatment (mean IIEF-EF: 14.9 and 11.1), followed by high confidence to get and maintain an erection (IIEF item 15: ≥3.5 and <3.5; IIEF-EF: 15.4 and 7.1). For patients meeting these criteria, additional non-IIEF–related predictors included robot-assisted laparoscopic surgery (yes or no; IIEF-EF: 19.3 and 12.6), quality of nerve sparing (NSS: <2.5 and

Sildenafil activates antioxidant and antiapoptotic genes and inhibits proinflammatory cytokine genes in a rat model of renal ischemia/reperfusion injury.

PubMed

Zahran, Mohamed H; Hussein, Abdelaziz M; Barakat, Nashwa; Awadalla, Amira; Khater, Shery; Harraz, Ahmed; Shokeir, Ahmed A

2015-11-01

To study the possible renoprotective effect of sildenafil against renal ischemia/reperfusion (I/R) injury and its effect on the expression of some antioxidant, antiapoptotic gene and proinflammatory cytokine genes in rat model of renal I/R injury. One hundred and twenty male Sprague Dawley rats were subdivided into three equal groups: sham (underwent right nephrectomy without ischemia), control (underwent right nephrectomy and left ischemia for 45 min) and study [as control with 1 mg/kg sildenafil (per oral) 60 min before anesthesia]. Serum creatinine and BUN were measured at the baseline and the study endpoints (2, 24, 48 h and 7 days), and the left kidney was harvested at study endpoints for histopathological examination as well as for assessment of the expression of antioxidant genes (Nrf-2, HO-1 and NQO-1), antiapoptotic gene (Bcl-2) and inflammatory cytokines, e.g., TNF-a, IL-1β and ICAM-1. I/R caused significant increase in serum creatinine, BUN, histopathological damage score (p < 0.001) and significant reduction in antioxidant genes (nrf2, HO-1 and NQO-1) and antiapoptotic gene (Bcl2) with significant increase in TNF-a, IL-1β and ICAM-1 genes in kidney tissues. Pretreatment with sildenafil caused significant attenuation of serum creatinine and BUN as well as significant increase in the expression of antioxidant genes and Bcl-2 genes with significant reduction in the expression of proinflammatory cytokine genes (p value < 0.001). The renoprotective effect of sildenafil against renal I/R might be due to the activation of antioxidant genes (Nrf2, HO-1 and NQO-1) and antiapoptotic gene (Bcl2) and attenuation of proinflammatory cytokines (TNF-a, IL-1β and ICAM-1).

Evidence for the efficacy and safety of tadalafil and finasteride in combination for the treatment of lower urinary tract symptoms and erectile dysfunction in men with benign prostatic hyperplasia

PubMed Central

Olesovsky, Chris; Kapoor, Anil

2016-01-01

Benign prostatic hyperplasia (BPH) is an age-related phenomenon associated with prostatic enlargement and bladder outlet obstruction that can cause significant lower urinary tract symptoms (LUTS). These LUTS have a negative impact on an individual’s quality of life, which is why treatment of symptomatic BPH has become a major priority. Although surgical interventions exist for treating BPH, pharmacological therapies are often preferred due to their minimal invasiveness and high degree of effectiveness. The three classes of drugs approved for treating BPH include α-blockers, 5-α-reductase inhibitors (5-ARIs) and phosphodiesterase 5 (PDE-5) inhibitors. Individually, each class of drug has been studied and shown to improve symptom relief through a variety of different mechanisms. A more recent focus has been on the development of combinatorial therapies that combine classes of drugs in order to provide maximal benefit. The mTOPS and CombAT studies were the first of their kind to examine whether the combination of 5-ARIs and α-blockers was more effective than monotherapy alone. Both studies found similar results in that the combinatorial therapy was superior to monotherapy. Over the last decade other combinatorial therapies have been at the forefront of investigation. One in particular is the combination of tadalafil, a PDE-5 inhibitor, with finasteride, a 5-ARI. Studies have shown that the combination of tadalafil and finasteride is a safe, effective, and well tolerated treatment for BPH. Evidence suggests that this combination may be particularly effective in reducing treatment-related sexual adverse events associated with 5-ARI treatments. The following review will explore in detail the current evidence surrounding treatment of BPH LUTS using tadalafil and finasteride. PMID:27928428

Neuroimaging Cerebrovascular Function and Diffuse Axonal Injury after Traumatic Brain Injury and Response to Sildenafil Treatment

DTIC Science & Technology

2016-04-05

pathoanatomic classification of TBI focusing on two mechanisms, and demonstrates assessment of mechanism-specific therapy . Our results suggest that sildenafil... therapies . x TABLE OF CONTENTS LIST OF TABLES...mechanism-specific targeted therapies (28; 61; 106). At the time of the primary injury, rapid acceleration-decceleration of the head causes

Ocular perfusion pressure and color Doppler imaging of the external ophthalmic artery of rabbits treated with sildenafil citrate.

PubMed

Costa, Ana Paula Araujo; Lima, Aline Maria Vasconcelos; da Silva, Luiz Henrique; de Oliveira Alves Carvalho, Rosângela; do Amaral, Andréia Vitor Couto; Borges, Naida Cristina

2016-07-22

It has been proposed that sildenafil citrate can increase ocular blood flow, and that this property can be used to treat ocular disorders that involve reflex vasoconstriction. This study therefore proposes to ascertain the vasodilator effect of the drug on retrobulbar circulation in healthy rabbits. For this matter rabbits treated with sildenafil citrate or saline solution had their intraocular pressure (IOP), mean arterial pressure (MAP), ocular perfusion pressure (OPP) and color Doppler imaging of the external ophthalmic artery measured prior to treatment and on days one (moment M1), seven (when M2), fourteen (moment M3), twenty-one (moment M4), and thirty (moment M5) of treatment. The MAP and OPP values of treated group were lower than those of control group at all times, and the mean values differed statistically at moments M1 (S = 71.52 mmHg, C = 84.76 mmHg, p = 0.0356) and M5 (S = 71.38 mmHg, C = 85.52 mmHg, p = 0.0252). The IOP and color Doppler values of the external ophthalmic artery did not differ between tested groups. The dose of 10 mg of sildenafil citrate administered to healthy rabbits causes systemic vasodilation and consequently lower values of MAP and OPP. However, it does not induce changes in IOP and retrobulbar hemodynamics identifiable by color Doppler assessment of the external ophthalmic artery.

Sildenafil Therapy Normalizes the Aberrant Metabolomic Profile in the Comt−/− Mouse Model of Preeclampsia/Fetal Growth Restriction

PubMed Central

Stanley, Joanna L.; Sulek, Karolina; Andersson, Irene J.; Davidge, Sandra T.; Kenny, Louise C.; Sibley, Colin P.; Mandal, Rupasri; Wishart, David S.; Broadhurst, David I.; Baker, Philip N.

2015-01-01

Preeclampsia (PE) and fetal growth restriction (FGR) are serious complications of pregnancy, associated with greatly increased risk of maternal and perinatal morbidity and mortality. These complications are difficult to diagnose and no curative treatments are available. We hypothesized that the metabolomic signature of two models of disease, catechol-O-methyl transferase (COMT−/−) and endothelial nitric oxide synthase (Nos3−/−) knockout mice, would be significantly different from control C57BL/6J mice. Further, we hypothesised that any differences in COMT−/− mice would be resolved following treatment with Sildenafil, a treatment which rescues fetal growth. Targeted, quantitative comparisons of serum metabolic profiles of pregnant Nos3−/−, COMT−/− and C57BL/6J mice were made using a kit from BIOCRATES. Significant differences in 4 metabolites were observed between Nos3−/− and C57BL/6J mice (p < 0.05) and in 18 metabolites between C57BL/6J and COMT−/− mice (p < 0.05). Following treatment with Sildenafil, only 5 of the 18 previously identified differences in metabolites (p < 0.05) remained in COMT−/− mice. Metabolomic profiling of mouse models is possible, producing signatures that are clearly different from control animals. A potential new treatment, Sildenafil, is able to normalize the aberrant metabolomic profile in COMT−/− mice; as this treatment moves into clinical trials, this information may assist in assessing possible mechanisms of action. PMID:26667607

2017 ACC/AAP/AHA Health Policy Statement on Opportunities and Challenges in Pediatric Drug Development: Learning From Sildenafil

PubMed Central

Sable, Craig A.; Ivy, D. Dunbar; Beekman, Robert H.; Clayton-Jeter, Helene D.; Jenkins, Kathy J.; Mahle, William T.; Morrow, William R.; Murphy, Mary Dianne; Nelson, Robert M.; Rosenthal, Geoffrey L.; Stockbridge, Norman; Wessel, David L.

2017-01-01

The STARTS-1 and -2 trials (Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension) and subsequent 2012 U.S. Food and Drug Administration (FDA) product labeling for sildenafil use in pediatric patients with pulmonary hypertension highlight many of the challenges to the development and approval of medications for children. This experience served as the impetus for direct collaboration between FDA representatives and the Joint Council on Congenital Heart Disease (JCCHD) (representing the pediatric cardiology leadership of the American College of Cardiology, the American Heart Association, and the American Academy of Pediatrics) to improve communication and realign missions with regard to pediatric drug trials. These discussions led to the joint FDA/JCCHD development of this statement, which describes the current environment and identifies possible future directions for reducing barriers to pediatric drug trials. PMID:28663437

[Sildenafil use and relevant risk factors among middle-aged or elderly male clients of female commercial sex workers in the central areas of Guangxi, China].

PubMed

Lu, Huaxiang; Tang, Zhenzhu; Shen, Zhiyong; Wu, Xinghua; Zhu, Qiuying; Chen, Huanhuan; Luo, Liuhong; Chen, Li

2014-11-01

To understand the illegal sidenafil use among middle-aged and elderly male clients of female sex workers (FSWs) in central region of Guangxi as well as on related risk factors. Initial evaluation regarding the effect of illegal sidenafil use on HIV infection among the middle-aged and elderly men was also conducted. A survey was conducted among the over 50-year-olds male clients of low-grade prostitutions in central areas of Guangxi. Information on demographics, related behavior, and illegal sidenafil use was collected. 5 ml blood sample were taken to test antibodies of HIV and syphilis. PASW Statistics 18.0 was used for data analysis. 2 056 questionnaires were completed. 23.1% of the participants said they had ever used illegal sidenafil. The risk of sildenafil use was low among the male clients who were not over 60 years old (OR = 0.586, 95% CI:0.459-0.749). The risks of sildenafil use among the male clients with frequencies(in the past 30 days) of having commercial sex behavior were:only once (OR = 0.184, 95%CI:0.090- 0.378), twice (OR = 0.187, 95%CI:0.089-0.378) or three times (OR = 0.181, 95%CI: 0.085-0.384) lower than those with more than five times. Being single (OR = 0.608, 95% CI: 0.396-0.933), married/cohabiting (OR = 0.533, 95% CI:0.391-0.727), having unstable partners (OR = 0.558, 95%CI:0.393-0.792) seemed to be protective on those who used sildenafil, among the study population. Factors as 'never use the condom (OR = 1.642, 95%CI:1.125-2.397) or 'seldom use as condom (OR = 1.840, 95%CI:1.278-2.648) when having commercial sex, were under high risk among the sildenafil users. Forty-seven subjects were HIV positive, with the prevalence as 2.29% in this study population. Male clients of the FSWs who used sidenafil were under 60 years of age and with higher risk of HIV infection. people who were ≥60 years old, divorced/widowed/ separated, with frequencies (in the past 30 days) of having commercial sex more than 5 times, never or occasionally using a condom

Efficacies of Papaverine and Sildenafil in the Treatment of Erectile Dysfunction in Early-Stage Paraplegic Men

ERIC Educational Resources Information Center

Yildiz, Necmettin; Gokkaya, Nilufer Kutay Ordu; Koseoglu, Fusun; Gokkaya, Serkan; Comert, Didem

2011-01-01

The aim of the study was to determine which vasoactive agent was more efficacious for erectile dysfunction (ED), intracavernosal papaverine or oral sildenafil, in paraplegic men within the first year after injury by using a penile color Doppler ultrasound as a quantitative imaging method and to determine the association between responses to these…

Effect of sildenafil citrate (Viagra) and ethanol on the Albino rat testis: a scanning electron microscopic approach.

PubMed

Sivasankaran, T G; Udayakumar, R; Elanchezhiyan, C; Sabhanayakam, Selvi

2008-02-01

The effects of sildenafil citrate with ethanol on the rat testis was studied using scanning electron microscopy. Male Albino rats were divided into 8 groups, each being treated for a maximum of 45 days as follows. In the 4 short-term treatment groups, control rats were administered normal saline orally, whereas experimental animals were fed sildenafil citrate (Viagra) 1 microg/g with 18% ethanol (5 g/kg body weight), which was given orally as a single dose. After 1, 2.5, 4 and 24h the rats were killed. In the 4 long-term treatment groups, daily continuous doses of drug and ethanol with a single dosage were given for 15, 30 and 45 days and the animals killed 4h after the last dosage. Changes in the testis were compared with the normal healthy rat testis. The use of a scanning electron microscope for evaluation of the changes in the testis is more suitable for observation of the surface and morphological shapes of the tissue structures.

Prospective, open-label, uncontrolled pilot study to study safety and efficacy of sildenafil in systemic sclerosis-related pulmonary artery hypertension and cutaneous vascular complications.

PubMed

Kumar, Uma; Sankalp, Gokhale; Gokhle, Sankalp S; Sreenivas, V; Kaur, Satbir; Misra, Durgaprasanna

2013-04-01

Pulmonary artery hypertension (PAH) remains the leading cause of morbidity and mortality in systemic sclerosis, while Raynaud's phenomenon and digital ulcers significantly add to the morbidity in systemic sclerosis (SSc). This study was undertaken to evaluate the role of sildenafil in PAH, Raynaud's phenomenon, and digital ulcers in systemic sclerosis patients. A prospective, open-label, uncontrolled pilot study was done at a tertiary care centre in India to study the safety and efficacy of oral sildenafil in PAH, Raynaud's phenomenon, digital infarcts, and ulcers in SSc. Seventeen patients fulfilling ACR classification criteria for scleroderma and having PAH were recruited. Six-minute walk test, WHO class of dyspnoea, severity of Raynaud's phenomenon, and 2D ECHO were performed in all the study subjects at baseline and at 3 months post-treatment. All patients were treated with oral sildenafil 25 mg three times a day for a period of 3 months. The pre- and post-treatment values of mean pulmonary artery pressure (PAP), 6-min walk test, WHO class of dyspnoea, and severity of Raynaud's phenomenon were compared to look for any significant change. Sixteen patients who completed 3-month follow-up had shown statistically significant improvement in 6-min walk test, WHO class of dyspnoea, severity of Raynaud's phenomenon, and mPAP. Also, there was no occurrence of new digital infarcts or ulcers, and existing ulcers showed signs of healing. Sildenafil is highly efficacious cheaper and safe alternative to other available therapies for SSc-associated PAH, Raynaud's phenomenon, and digital infarcts/ulcers.

Sildenafil Citrate for Prophylaxis of Nephropathy in an Animal Model of Contrast-Induced Acute Kidney Injury

PubMed Central

Lauver, D. Adam; Carey, E . Grant; Bergin, Ingrid L.; Lucchesi, Benedict R.; Gurm, Hitinder S.

2014-01-01

Contrast-induced acute kidney injury (CIAKI) is one of the commonest complications associated with contrast media (CM). Although the exact etiology of CIAKI remains unclear, one hypothesis involves vasoconstriction of afferent arterioles resulting in renal ischemia. Increased renal blood flow, therefore, might represent an attractive target for the treatment of CIAKI. In this study we evaluated the protective effects of the phosphodiesterase type 5 (PDE5) inhibitor, sildenafil citrate, in a rabbit model of CIAKI. New Zealand white rabbits were used due to their susceptibility to CIAKI. To evaluate the effects of sildenafil, the drug was administered before CM infusion and repeatedly throughout the remainder of the experiment (6 mg/kg, p.o.). Animals were sacrificed after 48 hours and kidneys were prepared for histological evaluation. Intravenous administration of CM produced marked kidney injury. Serum creatinine concentrations were elevated within two hours of the infusion and remained elevated for the duration of the experiment. Histological evaluation of the kidneys revealed significant tubular necrosis. The effects of the CM were dose dependent. Treatment with sildenafil was associated with lesser degree of histological injury, attenuation in markers of acute kidney injury (48 hour creatinine 1.54±0.21 versus 4.42±1.31 mg/dl, p<0.05) and reduction in electrolyte derangement (percent change in serum K+ at 48 hours 2.55±3.80% versus 15.53±4.47%, p<0.05; serum Na+ at 48 hours −0.14±0.26% versus −1.97±1.29%, p = 0.20). The results suggest a possible role for PDE5 inhibitors in the treatment of CIAKI and warrant further evaluation to determine the exact mechanism of protection. PMID:25426714

Sildenafil citrate for prophylaxis of nephropathy in an animal model of contrast-induced acute kidney injury.

PubMed

Lauver, D Adam; Carey, E Grant; Bergin, Ingrid L; Lucchesi, Benedict R; Gurm, Hitinder S

2014-01-01

Contrast-induced acute kidney injury (CIAKI) is one of the commonest complications associated with contrast media (CM). Although the exact etiology of CIAKI remains unclear, one hypothesis involves vasoconstriction of afferent arterioles resulting in renal ischemia. Increased renal blood flow, therefore, might represent an attractive target for the treatment of CIAKI. In this study we evaluated the protective effects of the phosphodiesterase type 5 (PDE5) inhibitor, sildenafil citrate, in a rabbit model of CIAKI. New Zealand white rabbits were used due to their susceptibility to CIAKI. To evaluate the effects of sildenafil, the drug was administered before CM infusion and repeatedly throughout the remainder of the experiment (6 mg/kg, p.o.). Animals were sacrificed after 48 hours and kidneys were prepared for histological evaluation. Intravenous administration of CM produced marked kidney injury. Serum creatinine concentrations were elevated within two hours of the infusion and remained elevated for the duration of the experiment. Histological evaluation of the kidneys revealed significant tubular necrosis. The effects of the CM were dose dependent. Treatment with sildenafil was associated with lesser degree of histological injury, attenuation in markers of acute kidney injury (48 hour creatinine 1.54±0.21 versus 4.42±1.31 mg/dl, p<0.05) and reduction in electrolyte derangement (percent change in serum K+ at 48 hours 2.55±3.80% versus 15.53±4.47%, p<0.05; serum Na+ at 48 hours -0.14±0.26% versus -1.97±1.29%, p = 0.20). The results suggest a possible role for PDE5 inhibitors in the treatment of CIAKI and warrant further evaluation to determine the exact mechanism of protection.

Phosphodiesterase 4 inhibitor and phosphodiesterase 5 inhibitor combination therapy has antifibrotic and anti-inflammatory effects in mdx mice with Duchenne muscular dystrophy.

PubMed

Nio, Yasunori; Tanaka, Masayuki; Hirozane, Yoshihiko; Muraki, Yo; Okawara, Mitsugi; Hazama, Masatoshi; Matsuo, Takanori

2017-12-01

Duchenne muscular dystrophy (DMD) is the most common inherited muscular dystrophy. Patients experience DMD in their 20s from cardiac or respiratory failure related to progressive muscle wasting. Currently, the only treatments for the symptoms of DMD are available. Muscle fibrosis, a DMD feature, leads to reduced muscle function and muscle mass, and hampers pharmaceutical therapeutic efficacy. Although antifibrotic agents may be useful, none is currently approved. Phosphodiesterase 4 (PDE4) inhibitors have exhibited antifibrotic effects in human and animal models. In this study, we showed beneficial effects of the PDE4 inhibitor piclamilast in the DMD mdx mouse. Piclamilast reduced the mRNA level of profibrotic genes, including collagen 1A1, in the gastrocnemius and diaphragm, in the mdx mouse, and significantly reduced the Sirius red staining area. The PDE5 inhibitors sildenafil and tadalafil ameliorated functional muscle ischemia in boys with DMD, and sildenafil reversed cardiac dysfunction in the mdx mouse. Single-treatment piclamilast or sildenafil showed similar antifibrotic effects on the gastrocnemius; combination therapy showed a potent antifibrotic effect, and piclamilast and combination therapy increased peroxisome proliferator-activated receptor γ coactivator-1α mRNA in mouse gastrocnemius. In summary, we confirmed that piclamilast has significant antifibrotic effects in mdx mouse muscle and is a potential treatment for muscle fibrosis in DMD.-Nio, Y., Tanaka, M., Hirozane, Y., Muraki, Y., Okawara, M., Hazama, M., Matsuo, T. Phosphodiesterase 4 inhibitor and phosphodiesterase 5 inhibitor combination therapy has antifibrotic and anti-inflammatory effects in mdx mice with Duchenne muscular dystrophy. © FASEB.

Ocular safety of sildenafil citrate when administered chronically for pulmonary arterial hypertension: results from phase III, randomised, double masked, placebo controlled trial and open label extension

PubMed Central

Tressler, Charles; Hwang, Lie-Ju; Burgess, Gary; Laties, Alan M

2012-01-01

Objective To assess the ocular effects and safety profile of chronic sildenafil oral dosing in patients with pulmonary arterial hypertension. Design 12 week, double masked, randomised, placebo controlled, phase III trial with open label extension. Setting 53 institutions worldwide. Participants 277 adults with idiopathic pulmonary arterial hypertension or pulmonary arterial hypertension associated with connective tissue disease or after congenital heart disease repair (mean pulmonary artery pressure ≥25 mm Hg; pulmonary capillary wedge pressure ≤15 mm Hg at rest). Interventions During the double masked study, oral sildenafil 20 mg, 40 mg, or 80 mg or placebo (1:1:1:1) three times daily for 12 weeks was added to baseline drug treatment. In the extension study, the placebo, 20 mg and 40 mg groups received 40 mg three times daily titrated to 80 mg three times daily at week 6. After unmasking, the dose was titrated according to clinical need. Main outcome measure Ocular safety (ocular examinations, visual function tests, participants’ reports of adverse events, and visual disturbance questionnaire completed by investigators) by treatment group at 12 weeks, 24 weeks, 18 months, and yearly. Results Findings of the objective assessments—that is, intraocular pressure and visual function tests (visual acuity, colour vision, and visual field)—were similar across groups (20 mg, n=69; 40 mg, n=67; 80 mg, n=71; placebo, n=70). No clinically significant changes occurred between baseline and 12 weeks, except for an efficacy signal in contrast sensitivity for the sildenafil 40 mg three times daily group. In right eyes, changes in intraocular pressure from baseline to week 12 ranged from a mean of −0.5 (95% confidence interval −1.3 to 0.2) mm Hg with placebo, −0.2 (−0.9 to 0.5) mm Hg with sildenafil 40 mg, and −0.1 (−0.7 to 0.5) mm Hg with 80 mg to 0.3 (−0.4 to 0.9) mm Hg with sildenafil 20 mg (the approved dose for pulmonary arterial hypertension). Mean

Adherence to Phosphodiesterase Type 5 Inhibitors in the Treatment of Erectile Dysfunction in Long-Term Users: How Do Men Use the Inhibitors?

PubMed Central

Carvalheira, Ana; Forjaz, Vera; Pereira, Nuno Monteiro

2014-01-01

Introduction The high effectiveness of phosphodiesterase type 5 inhibitors (PDE5-i) in the treatment of erectile dysfunction (ED) has been demonstrated. However, previous research shows that PDE5-i treatments have high discontinuation rates. Aim The main goals of this study were to (i) characterize the way men use PDE5-i and (ii) analyze the adherence to treatment, identifying the factors that influence PDE5-i use. Methods A total of 148 men with clinical diagnosis for ED who maintained the treatment with PDE5-i for over 3 years were interviewed. Interviews concerning their ongoing treatment were carried out using a standardized questionnaire with quantitative and qualitative items. Main Outcome Measures Physiological measures included the intracavernous alprostadil injection test, associated with penile rigidometry and penile Doppler ultrasound. The qualitative measure included two questions: “Do you use the drug in every sexual intercourse?” and “How do you use the inhibitor?” Results ED causes were classified as venogenic (31%), arteriogenic (23%), psychogenic (18%), iatrogenic (13%), neurogenic (8%), and diabetic (7%). Participation rate was 71.8%. Of the 148 patients studied, 75% claimed not to use PDE5-i in every intercourse. Most used tadalafil (66%), followed by sildenafil (20%), vardenafil (10%), and 4% alternated the type of medicine. Four main categories emerged concerning the factors that determine the intake of PDE5-i in some intercourse situations and not in others: (i) psychological factors; (ii) medication-related factors; (iii) circumstantial factors; and (iv) relational factors. Conclusion The analysis of men's narratives revealed a combination of factors that influence the adherence to PDE5-i. The psychological and medication-related factors were the most prevalent. This study highlighted the importance of taking these factors into account, both at the time of prescription and during the follow-up in order to improve adherence

Solid-phase extraction assisted dispersive liquid-liquid microextraction based on solidification of floating organic droplet to determine sildenafil and its analogues in dietary supplements.

PubMed

Li, Jing; Roh, Si Hun; Shaodong, Jia; Hong, Ji Yeon; Lee, Dong-Kyu; Shin, Byong-Kyu; Park, Jeong Hill; Lee, Jeongmi; Kwon, Sung Won

2017-08-01

A novel analytical method for the simultaneous determination of the concentration of sildenafil and its five analogues in dietary supplements using solid-phase extraction assisted reversed-phase dispersive liquid-liquid microextraction based on solidification of floating organic droplet combined with ion-pairing liquid chromatography with an ultraviolet detector was developed. Parameters that affect extraction efficiency were systematically investigated, including the type of solid-phase extraction cartridge, pH of the extraction environment, and the type and volume of extraction and dispersive solvent. The method linearity was in the range of 5.0-100 ng/mL for sildenafil, homosildenafil, udenafil, benzylsildenafil, and thiosildenafil and 10-100 ng/mL for acetildenafil. The coefficients of determination were ≥0.996 for all regression curves. The sensitivity values expressed as limit of detection were between 2.5 and 7.5 ng/mL. Furthermore, intraday and interday precisions expressed as relative standard deviations were less than 5.7 and 9.9%, respectively. The proposed method was successfully applied to the analysis of sildenafil and its five analogues in complex dietary supplements. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Penile histomorphometrical evaluation in hypertensive rats treated with sildenafil or enalapril alone or in combination: a comparison with normotensive and untreated hypertensive rats.

PubMed

Felix-Patrício, Bruno; Medeiros, Jorge L; De Souza, Diogo B; Costa, Waldemar S; Sampaio, Francisco J B

2015-01-01

Erectile dysfunction (ED) is frequently associated to hypertension and antihypertensive drugs; however, the penile morphological aspects on these situations are poorly known. Evaluate the penile morphology of untreated hypertensive rats and rats treated with enalapril or sildenafil alone or in combination to verify the hypothesis that morphological alterations promoted by hypertension on corpus cavernosum could be ameliorated by the use of angiotensin-converting enzyme inhibitors and/or phosphodiesterase type 5 inhibitors. Fifty male rats were assigned into five groups: normotensive rats, untreated spontaneously hypertensive rats (SHRs), and SHR treated with enalapril or sildenafil alone or in combination. Blood pressure was measured weekly. At the conclusion of the study, the rats were euthanized, and their penises were collected for histomorphometrical analysis. The cross-sectional areas of the penis, tunica albuginea, and corpus cavernosum were measured. The density of the corpus cavernosum structures was quantified. Both groups of SHR rats treated with enalapril became normotensive. Untreated SHR showed no difference in penile and cavernosal cross-sectional area compared with normotensive rats; however, those rats treated with enalapril or sildenafil alone demonstrated an increase in these parameters. Rats receiving combination therapy showed no cross-sectional area differences compared with normotensive rats. Cavernosal connective tissue density was increased, while the sinusoidal spaces were diminished in untreated SHR. All treatments were effective in maintaining connective tissue density in comparison with normotensive animals. Cavernosal smooth muscle density was similar in all groups, with the exception of the combination therapy group, which demonstrated a reduction in smooth muscle. Hypertension promoted structural alterations in the corpus cavernosum that may be related to ED. Enalapril- and sildenafil-treated animals had preservation of normal corpus

Development and implementation of a pass/fail field-friendly method for detecting sildenafil in suspect pharmaceutical tablets using a handheld Raman spectrometer and silver colloids.

PubMed

Lanzarotta, Adam; Lorenz, Lisa; Batson, JaCinta S; Flurer, Cheryl

2017-11-30

A simple, fast, sensitive and effective pass/fail field-friendly method has been developed for detecting sildenafil in suspect Viagra and unapproved tablets using handheld Raman spectrometers and silver colloids. The method involves dissolving a portion of a tablet in water followed by filtration and addition of silver colloids, resulting in a solution that can be measured directly through a glass vial. Over one hundred counterfeit Viagra and unapproved tablets were examined on three different devices during the method development phase of the study. While the pass/fail approach was found to be 92.6% effective on average, the efficacy increased to 97.4% on average when coupled with the software's "Discover Mode" feature that allows the user to compare a suspect spectrum to that of a stored sildenafil spectrum. The lowest concentration of sildenafil in a water/colloid solution that yielded a "Pass" was found to be 7.6μg/mL or 7.6 parts per million (ppm). For the analysis of suspect tablets, this value was found to be as low as 10μg/mL and as high as 625μg/mL. This variability was likely related to the tablet formulation, e.g., concentration of sildenafil, presence and concentration of water-soluble and/or water-insoluble ingredients. However, since most counterfeit Viagra and unapproved tablets contain >50mg sildenafil per tablet, such low concentrations will not be encountered often. Limited in-lab and in-field validation studies were conducted in which analysts/field agents followed the procedure outlined in this study for small sample sets. These individuals were provided with written instructions, a ∼20min demonstration regarding how to perform the procedure and use the instrument, and a kit with field-friendly supplies (purified bottled water from a local grocery store, disposable plastic pipettes, eye-dropper with a silver colloid solution, etc.). The method proved to be 98.3% and 91.7% effective for the in-lab and in-field validation studies

Polyamidoamine (PAMAM) dendrimers as potential release modulators and oral bioavailability enhancers of vardenafil hydrochloride.

PubMed

Tawfik, Mai Ahmed; Tadros, Mina Ibrahim; Mohamed, Magdy Ibrahim

2018-05-21

Vardenafil hydrochloride (VAR) is an erectile dysfunction treating drug. VAR has a short elimination half-life (4-5 h) and suffers low oral bioavailability (15%). This work aimed to explore the dual potential of VAR-dendrimer complexes as drug release modulators and oral bioavailability enhancers. VAR-dendrimer complexes were prepared by solvent evaporation technique using four dendrimer generations (G4.5, G5, G5.5 and G6) at three concentrations (190 nM, 380 nM and 950 nM). The systems were evaluated for intermolecular interactions, particle size, zeta potential, drug entrapment efficiency percentages (EE%) and drug released percentages after 2 h (Q 2h ) and 24 h (Q 24h ). The results were statistically analyzed, and the system showing the highest desirability was selected for further pharmacokinetic studies in rabbits, in comparison to Levitra ® tablets. The highest desirability (0.82) was achieved with D10 system comprising VAR (10 mg) and G6 (190 nM). It possessed small particle size (113.85 nm), low PDI (0.19), positive zeta potential (+21.53), high EE% (75.24%), promising Q 2 h (41.45%) and Q 24 h (74.05%). Compared to Levitra ® tablets, the significantly (p < 0.01) delayed T max , prolonged MRT (0-∞) and higher relative bioavailability (3.7-fold) could clarify the dual potential of D10 as a sustained release system capable of enhancing VAR oral bioavailability.

Beneficial long term effect of a phosphodiesterase-5-inhibitor in cirrhotic portal hypertension: A case report with 8 years follow-up.

PubMed

Deibert, Peter; Lazaro, Adhara; Stankovic, Zoran; Schaffner, Denise; Rössle, Martin; Kreisel, Wolfgang

2018-01-21

Non-selective beta-blockers are the mainstay of medical therapy for portal hypertension in liver cirrhosis. Inhibitors of phosphodiesterase-5 (PDE-5-inhibitors) reduce portal pressure in the acute setting by > 10% which may suggest a long-term beneficial effect. Currently, there is no available data on long-term treatment of portal hypertension with PDE-5-inhibitors. This case of a patient with liver cirrhosis secondary to autoimmune liver disease with episodes of bleeding from esophageal varices is the first documented case in which a treatment with a PDE-5-inhibitor for eight years was monitored. In the acute setting, the PDE-5-inhibitor Vardenafil lowered portal pressure by 13%. The portal blood flow increased by 28% based on Doppler sonography and by 16% using MRI technique. As maintenance medication the PDE-5-inhibitor Tadalafil was used for eight consecutive years with comparable effects on portal pressure and portal blood flow. There were no recurrence of bleeding and no formation of new varices. Influencing the NO-pathway by the use of PDE-5 inhibitors may have long-term beneficial effects in compensated cirrhosis.

A multicenter, double-blind, placebo-controlled study of sildenafil citrate in Canadian men with erectile dysfunction and untreated symptoms of depression, in the absence of major depressive disorder.

PubMed

Kennedy, Sidney H; Dugré, Hélène; Defoy, Isabelle

2011-05-01

Depression and erectile dysfunction (ED) often co-occur. Phosphodiesterase type 5 inhibitors are effective in men with ED and untreated depression, or ED secondary to antidepressants. This study evaluated sildenafil treatment in Canadian men with clinically diagnosed ED (Sexual Health Inventory for Men score ≤ 21) and mild-to-moderate untreated depressive symptoms [Beck Depression Inventory II (BDI-II) score 14-28], but excluding major depressive disorder. Pretreatment screening using the Sexual Health Inventory for Men and BDI-II showed that men with ED were more likely to have depression than men without ED, and ED severity was a predictor of depression (P=0.0226). Two hundred and two men were randomized to 6 weeks of double-blind treatment with placebo (n=98) or sildenafil (n=104), initial dose of 50 mg, adjustable to 25 or 100 mg. The men were evaluated on all domains of the International Index of Erectile Function and the Sex Effects Questionnaire, Global Efficacy Questions, and Event-log data. Compared with placebo, patients treated with sildenafil had significantly greater changes from baseline in BDI-II scores (P<0.001). All International Index of Erectile Function domains and the Sex Effects Questionnaire components were also significantly improved in sildenafil group (P<0.01). The most common adverse events included headache, dyspepsia, vasodilatation, and respiratory tract infections and were generally mild in intensity. 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Role of nocturnal penile erection test on response to daily sildenafil in patients with erectile dysfunction due to pelvic fracture urethral disruption: a single-center experience.

PubMed

Peng, Jing; Zhang, Zhichao; Cui, Wanshou; Yuan, Yiming; Gao, Bing; Song, Weidong; Xin, Zhongcheng

2014-12-01

To evaluate the results of nocturnal penile erection test and response to daily sildenafil in patients with erectile dysfunction (ED) due to pelvic fracture urethral disruption. From January 2010 to January 2012, we included 38 patients with ED due to pelvic fracture urethral disruption. The mean age was 33.1 years (range, 22-49 years). All were evaluated subjectively and objectively by the International Index of Erectile Function-5, nocturnal penile tumescence and rigidity (NPTR) test, and penile Doppler ultrasonography. Patients received daily sildenafil 50 mg for 3 months. Thirty-one patients were followed up: 54.8% showed response to sildenafil defined as reporting successful vaginal penetration and intercourse. Patients with neurogenic, arterial, and venous EDs did not differ in efficiency rates (P = .587). However, the penile erectile rigidity recorded by NPTR test affected efficiency significantly (P = .046). Patients with tip rigidity >40% had the highest response rate (76.9%), but the response rate for patients with tip rigidity <20% was only 22.2%. NPTR recording can reveal resident erectile function in patients with ED due to trauma and is significant for selecting pharmacologic treatment as optimal therapy. Copyright © 2014 Elsevier Inc. All rights reserved.

Sildenafil ameliorates right ventricular early molecular derangement during left ventricular pressure overload.

PubMed

Imai, Yousuke; Kariya, Taro; Iwakiri, Masaki; Yamada, Yoshitsugu; Takimoto, Eiki

2018-01-01

Right ventricular (RV) dysfunction following left ventricular (LV) failure is associated with poor prognosis. RV remodeling is thought initiated by the increase in the afterload of RV due to secondary pulmonary hypertension (PH) to impaired LV function; however, RV molecular changes might occur in earlier stages of the disease. cGMP (cyclic guanosine monophosphate)-phosphodiesterase 5 (PDE5) inhibitors, widely used to treat PH through their pulmonary vasorelaxation properties, have shown direct cardiac benefits, but their impacts on the RV in LV diseases are not fully determined. Here we show that RV molecular alterations occur early in the absence of RV hemodynamic changes during LV pressure-overload and are ameliorated by PDE5 inhibition. Two-day moderate LV pressure-overload (transverse aortic constriction) neither altered RV pressure/ function nor RV weight in mice, while it induced only mild LV hypertrophy. Importantly, pathological molecular features were already induced in the RV free wall myocardium, including up-regulation of gene markers for hypertrophy and inflammation, and activation of extracellular signal-regulated kinase (ERK) and calcineurin. Concomitant PDE5 inhibition (sildenafil) prevented induction of such pathological genes and activation of ERK and calcineurin in the RV as well as in the LV. Importantly, dexamethasone also prevented these RV molecular changes, similarly to sildenafil treatment. These results suggest the contributory role of inflammation to the early pathological interventricular interaction between RV and LV. The current study provides the first evidence for the novel early molecular cross-talk between RV and LV, preceding RV hemodynamic changes in LV disease, and supports the therapeutic strategy of enhancing cGMP signaling pathway to treat heart diseases.

Pharmacologic therapy for erectile dysfunction and its interaction with the cardiovascular system.

PubMed

Ioakeimidis, Nikolaos; Kostis, John B

2014-01-01

Phosphodiesterase (PDE) enzymes are widely distributed throughout the body, having numerous effects and functions. The PDE type 5 (PDE5) inhibitors are widely used to treat erectile dysfunction (ED). Recent, intense preclinical and clinical research with PDE5 inhibitors has shed light on new mechanisms and has revealed a number of pleiotropic effects on the cardiovascular (CV) system. To date, PDE5 inhibition has been shown to be effective for the treatment of idiopathic pulmonary arterial hypertension, and both sildenafil and tadalafil are approved for this indication. However, current or future PDE5 inhibitors have the potential of becoming clinically useful in a variety of CV conditions such as heart failure, coronary artery disease, and hypertension. The present review discusses recent findings regarding pharmacologic treatment of ED and its interaction with the CV system and highlights current and future clinical applications beyond ED.

Effects of tadalafil on ischemia/reperfusion injury in rat brain.

PubMed

Altaş, Murat; Aras, M; Meydan, S; Nacar, E; Ulutaş, K T; Serarslan, Y; Yılmaz, N

2014-03-01

Cerebral ischemia-reperfusion (I/R) injury is caused by lack of blood supply to the brain. The accumulation of toxic products such as reactive oxygen species (ROS) occurs on reperfusion, when the occlusion is removed. The resulting oxidative stress results in the initiation of pathways leading to necrotic and apoptotic cell death. Tadalafil (TAD) prevents the accumulation of ROS and increases antioxidant cellular protective mechanisms. The aim of this study was to investigate the effect of TAD treatment against short-term global brain I/R injury in rats. The study was carried out on 30 Wistar-albino rats, which were divided into three groups including a control group (n = 10), an I/R group (n = 10) and an I/R + TAD group (n = 10) (2 mg/kg/day for 4 days before ischemia). At the end of the experiment, tissue samples were collected for both biochemical and histopathological analyses. Malondialdehyde was significantly lower in the TAD-administered group (9.06 ± 0.15) than in the I/R group (p < 0.05). However, no significant difference was observed in nitric oxide levels in the TAD-administered group compared to the I/R group. The mean superoxide dismutase level was significantly higher in the I/R-TAD group than the I/R group. There was no statistically significant difference in glutathione peroxidase levels in I/R + TAD group compared to I/R group. Histopathologically, TAD-administered group provided significant morphological improvement compared to the I/R group. We concluded that TAD prevented I/R-induced neurotoxicity as shown by obtained biochemical and histopathological findings.

Efficient synthesis of dichlorodenafil, an unapproved sildenafil analogue appearing in non-prescription supplements.

PubMed

Kim, Jong Yup; Hwang, In Gyun; Oh, Jae Ho; Kang, Il Hyun; Kwon, Sung Won; Kim, Deukjoon

2013-01-01

We have developed an efficient synthesis of dichlorodenafil (4), an unapproved sildenafil analogue isolated from dietary supplements. Our sequence employs POCl(3)-mediated chlorination of readily available chloroacetyl compound 7 followed by selective hydrolysis of the chloro-heterocycle function. Our synthesis confirms the structure of the illegal additive, and will provide regulatory agencies with ready access to authentic standard samples of dichlorodenafil (4) to aid in their mission to protect the public from unapproved and potentially harmful erectile dysfunction (ED) drug analogues that are added to herbal and dietary supplements without providing users with appropriate toxicological or pharmacological information.

A Novel Therapeutic Approach in the Treatment of Pulmonary Arterial Hypertension: Allium ursinum Liophylisate Alleviates Symptoms Comparably to Sildenafil

PubMed Central

Bombicz, Mariann; Priksz, Daniel; Varga, Balazs; Kurucz, Andrea; Kertész, Attila; Takacs, Akos; Posa, Aniko; Kiss, Rita; Szilvassy, Zoltan; Juhasz, Bela

2017-01-01

Right-sided heart failure—often caused by elevated pulmonary arterial pressure—is a chronic and progressive condition with particularly high mortality rates. Recent studies and our current findings suggest that components of Wild garlic (Allium ursinum, AU) may play a role in reducing blood pressure, inhibiting angiotensin-converting enzyme (ACE), as well as improving right ventricle function in rabbit models with heart failure. We hypothesize that AU may mitigate cardiovascular damage caused by pulmonary arterial hypertension (PAH) and has value in the supplementary treatment of the complications of the disease. In this present investigation, PAH was induced by a single dose of monocrotaline (MCT) injection in Sprague-Dawley rats, and animals were divided into 4 treatment groups as follows: I. healthy control animals (Control group); II. pulmonary hypertensive rats (PAH group); III. pulmonary hypertensive rats + daily sildenafil treatment (Sildenafil group); and IV. pulmonary hypertensive rats + Wild garlic liophylisate-enriched chow (WGLL group), for 8 weeks. Echocardiographic measurements were obtained on the 0 and 8 weeks with fundamental and Doppler imaging. Isolated working heart method was used to determinate cardiac functions ex vivo after thoracotomy on the 8th week. Histological analyses were carried out on excised lung samples, and Western blot technique was used to determine Phosphodiesterase type 5 enzyme (PDE5) expression in both myocardial and pulmonary tissues. Our data demonstrate that right ventricle function measured by echocardiography was deteriorated in PAH animals compared to controls, which was counteracted by AU treatment. Isolated working heart measurements showed elevated aortic flow in WGLL group compared to PAH animals. Histological analysis revealed dramatic increase in medial wall thickness of pulmonary arteries harvested from PAH animals, but arteries of animals in sildenafil- and WGLL-treated groups showed physiological status

A prospective, randomized, placebo-controlled trial of on-Demand vs. nightly sildenafil citrate as assessed by Rigiscan and the international index of erectile function.

PubMed

Kim, D J; Hawksworth, D J; Hurwitz, L M; Cullen, J; Rosner, I L; Lue, T F; Dean, R C

2016-01-01

Multiple studies have evaluated the use of PDE5 inhibitors in penile rehabilitation following nerve-sparing prostatectomy. These studies have evaluated the use of various pharmacologic agents as well as various approaches to treatment (on-demand vs. rehabilitative). Most of these studies relied on self-reported outcomes to determine efficacy of the therapy which could allow response bias to affect their results. The aim of this study was to evaluate the effects of nightly sildenafil citrate therapy during penile rehabilitation, using nocturnal penile rigidity (RigiScan(™), Gotop Medical, Inc., St. Paul, MN, USA) in addition to the IIEF-EF. Patients with localized prostate cancer and normal erectile function prior to nsRP were randomized to take either nightly 50 mg sildenafil citrate or placebo starting the night following surgery. Both groups were allowed on-demand sildenafil citrate. Erectile function was evaluated at 2 weeks, 3, 6, 9 and 12 months post-operatively, with a final assessment made at 13 months, following a 1 month drug washout. At all time points, self-reported (IIEF-EF) and objective (RigiScan(™)) measures were obtained and evaluated. About 74 of 97 randomized patients completed the study. On completion, 40% of patients in each group had normal erectile function based on RigiScan(™) (p = 1.0). Additionally, no statistical differences were seen using the IIEF-EF domain (32.4% of placebo, 29% of treatment; p = 0.79). Multivariable analysis showed no significant differences in erectile function based on treatment intervention. Results did show that African-American men in this cohort were at higher risk for lower RigiScan(™) scores over time (OR: 0.48, p = 0.0399). This study demonstrates that nightly sildenafil citrate does not provide a therapeutic benefit for recovery of erectile function post-prostatectomy when compared to on-demand dosing using both self-reported as well as objective measures. Differences in objective recovery parameters

The quality of sildenafil active substance of illegal source.

PubMed

Keizers, Peter H J; Wiegard, Andrea; Venhuis, Bastiaan J

2016-11-30

There must be a large market for active pharmaceutical ingredients of illegal source to support the huge and lucrative business of trade in illegal medicines. The active substances found in illegal pharmaceuticals may differ from their legal counterparts concerning purity and associated risks for the health of the user. In this study we show two examples in which the active substance sildenafil, used in erectile dysfunction products, was not of European Pharmacopeia quality. In one case milligram-scale amounts of a 2-mercaptobenzothiazole contamination were found, in another case the mesylate salt rather than the monograph based citrate was used. For the user of products containing these active substances, the risks of side effects increase through the inherent properties of the impurity and the chance of overdosing. The fact that the users are most likely not aware of the poor quality of the products adds up to the health risk of using prescription medication without consulting medical professionals. Copyright © 2016 Elsevier B.V. All rights reserved.

Assessing the impact of diclofenac, ibuprofen and sildenafil citrate (Viagra®) on the fertilisation biology of broadcast spawning marine invertebrates.

PubMed

Mohd Zanuri, Norlaila Binti; Bentley, Matthew G; Caldwell, Gary S

2017-06-01

Exposure to synthetic chemicals is a key environmental challenge faced by aquatic organisms. The time and dose effects of the pharmaceuticals diclofenac, ibuprofen, and sildenafil citrate on sperm motility and successful fertilisation are studied using the echinoderms, Asterias rubens and Psammechinus miliaris, and the polychaete worm Arenicola marina, all important components of the marine benthos. Motility was reduced for all species when exposed to diclofenac concentrations ≥0.1 μg/L. Exposure to ≥1.0 μg/L of ibuprofen affected only P. miliaris gametes and fertilisation success of A. marina. A. rubens and P. miliaris sperm increased in both percentage motility and swimming velocity when exposed to sildenafil citrate at concentrations ≥18 and ≥ 50 ng/L, respectively. Pre-incubation of sperm with sildenafil citrate significantly increased fertilisation success in A. rubens and P. miliaris but not in A. marina. Pre-incubated A. rubens oocytes fertilised successfully in ibuprofen. According to EU Directive 93/67/EEC, diclofenac is classified as a very toxic substance to gametes of A. rubens, P. miliaris, and A. marina (EC 50  = 100-1000 μg/L) while ibuprofen is classified as very toxic to gametes of P. miliaris but non-toxic to gametes of A. marina (EC 50  > 10,000 μg/L). The present study indicates that diclofenac exposure may have negative impacts on invertebrate reproductive success, whereas ibuprofen potentially may compromise P. miliaris reproduction. This study provides a valuable insight into the mechanisms that allow marine invertebrates to survive and reproduce in contaminated and changing habitats. Copyright © 2017 Elsevier Ltd. All rights reserved.

Comparison of the Effects of Elaeagnus angustifolia Flower Capsule and Sildenafil Citrate Tablet on Anxiety Resulting From Sexual Dysfunction in Women Referring to the Selected Clinics of Shiraz University of Medical Sciences.

PubMed

Zeinalzadeh, Sanaz; Akbarzadeh, Marzieh; Mohagheghzadeh, Abdolali; Faridi, Pouya; Sayadi, Mehrab

2016-07-01

Dissatisfaction from sexual relationships can result in deprivation as well as problems, such as depression, anxiety, and destruction of family's mental health. One hundred twenty-five women (18 to 40 years) who suffered from hypoactive sexual desire disorder were divided into Elaeagnus angustifolia flower (4.5 g g daily for 35 days), sildenafil citrate tablet (50 mg for 4 weeks), and control groups. The study data were collected using the Female Sexual Function Index and Spielberger's questionnaire and measurement of thyroid-stimulating hormone and prolactin hormone. In the Elaeagnus angustifolia group, the mean score of state and trait anxiety decreased after the intervention. In the sildenafil citrate group also, the mean score of state anxiety decreased from 22.15 ± 4.98 to 20.1 ± 5.15 (P = .001) and that of trait anxiety decreased from 23.07 ± 4.44 to 21.55 ± 4.82 (P = .002) after the intervention. Consumption of sildenafil citrate tablet was effective in reduction of the mean score of anxiety resulting from sexual dysfunction. © The Author(s) 2015.

Effect of sildenafil citrate on the male sexual experience assessed with the Sexual Experience Questionnaire: a multicenter, double-blind, placebo-controlled trial with open-label extension.

PubMed

Jones, LeRoy A; Klimberg, Ira W; McMurray, James G; Padula, Rebecca; Tseng, Li-Jung; Stecher, Vera J

2008-08-01

The Sexual Experience Questionnaire (SEX-Q) enables quick and easy assessment of functional, emotional, and satisfaction-related aspects of the sexual experience in men with erectile dysfunction (ED). To assess correlations between improvement on the SEX-Q and outcomes on other validated questionnaires. METHODS. Men with ED (score < or =25 on the Erectile Function domain of the International Index of Erectile Function [IIEF]) who had used less than or equal to six doses of any phosphodiesterase 5 inhibitor (none within 6 months) were randomized to 10 weeks of double-blind, placebo-controlled (DBPC) flexible-dose sildenafil citrate (50 or 100 mg, as needed), followed by 6 weeks of open-label (OL) sildenafil. SEX-Q, IIEF, Quality of Erection Questionnaire (QEQ), Self-Esteem and Relationship (SEAR) Questionnaire, Erection Hardness Score (EHS), successful intercourse attempts (SIAs), Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS), and global efficacy questions (GEQs). Compared with the placebo group (N = 105), the sildenafil group (N = 104) at DBPC end of treatment (EOT) had significantly more improvement (P < 0.05) on all SEX-Q, IIEF (except the Sexual Desire domain), QEQ, and SEAR outcomes, more frequent SIAs and EHS 3 (hard enough for penetration but not completely hard) or EHS 4 (completely hard) erections (odds ratio [OR], 2.52 and 3.46, respectively), EHS 4 erections four times as often (OR, 6.41), more men satisfied with treatment (EDITS; OR, 2.6), approximately twice as many men with improved erections (GEQ1; OR, 5.8) and ability to have sexual intercourse (GEQ2; OR, 5.4), and GEQ3 scores that indicated better sex (P < 0.0001). SEX-Q score improvements correlated positively with all other outcomes. At OL EOT, most outcomes were >60% (and approximately half were > or =80%) of the maximum positive result. SEX-Q change scores correlate with several other functional, emotional, and satisfaction-related outcomes in men treated with sildenafil for

Potential risk of developing herpes simplex encephalitis in patients treated with sildenafil following primary exposure to genital herpes.

PubMed

Goren, A; Mccoy, J; Kovacevic, M; Situm, M; Lonky, N

2017-01-01

Herpes simplex encephalitis (HSE) is associated with significant mortality and morbidity. As a consequence of HSE, up to 75% of infected individuals die or experience irreversible neurological damage. While the pathogenesis of the disease is unknown, it is traditionally hypothesized that the viral infection occurs by neuronal transmission directly from peripheral sites. Non-neuronal modes of infection have generally been overlooked as the brain is protected by the blood-brain-barrier (BBB). The BBB poses an effective barrier to pathogens as well as to drugs such as chemotherapies. In the pursuit to deliver chemotherapeutic agents to the brain, several studies demonstrated that phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil, may increase the permeability of the BBB enabling successful delivery of chemotherapeutic agents to the brain. In this communication, we report a case of HSE infection in a 62-year-old man, which we suspect was facilitated by the use of sildenafil during a primary genital herpes simple virus (HSV) infection. Due to large number of patients treated with PDE5 inhibitors for erectile dysfunction and the high incidence of genital HSV infection in the general population, a larger study should examine the potential risk of developing HSE in patients treated with PDE5 inhibitors.

Possible Role of Sildenafil Citrate in the Recurrence of Neovascularization in Laser-regressed Aggressive Posterior ROP.

PubMed

Jayadev, Chaitra; Ramasastry, Phanibhushan; Gul, Alia; Vinekar, Anand

2016-11-07

Systemic diseases and their treatment influence aggressive posterior retinopathy of prematurity. A premature infant with aggressive posterior retinopathy of prematurity underwent laser treatment with a favourable outcome. She was started on oral sidenafil citrate for pulmonary hypertension. Ten days later she developed neovascularization within the lasered retina. Considering the possible role of sildenafil in this unusual development, the drug was withdrawn resulting in regression of the neovascularization. The clinician should be aware of this retinal adverse effect of sildanefil in neonates with aggressive posterior retinopathy of prematurity.

The effect of lifestyle modification and glycemic control on the efficiency of sildenafil citrate in patients with erectile dysfunction due to type-2 diabetes mellitus.

PubMed

Kirilmaz, Utku; Guzel, Ozer; Aslan, Yilmaz; Balci, Melih; Tuncel, Altug; Atan, Ali

2015-01-01

We evaluated the effect of lifestyle modifications and glycemic control on the efficiency of sildenafil citrate in patients with type-2 diabetes (T2DM) and erectile dysfunction (ED). Eighty-three men with ED due to T2DM were included in the study. The Group 1 (n = 41) patients received lifestyle modifications (diet and exercise), and medical treatment for intensive glycemic control. In Group 2 (n = 42), in addition to the intensive glycemic control, the patients were given sildenafil citrate® 100 mg for 2-3 per weeks. The changes in ED were compared between the two groups after three months of treatment. The mean age was 54.9 ± 9.1 (26-75) years. An increase in the IIEF-5 scores was observed in 23 of 41 patients in Group 1 (44.2%) and 29 of 42 in Group 2 (55.8%). When the changes of the IIEF-5 scores were evaluated, the mean increase was 2.5 in Group 1, and 5.0 in Group 2 (p = 0.012). The mean IIEF changes according to the duration of diabetes were 4.8 in <5 years, 3.6 in 5-10 years and 1.6 in >10 years (p = 0.021). Glycemic control and lifestyle changes are not solely adequate for a better sexual function in ED due to diabetes, and sildenafil citrate should be used additionally.

Tadalafil alleviates muscle ischemia in patients with Becker muscular dystrophy.

PubMed

Martin, Elizabeth A; Barresi, Rita; Byrne, Barry J; Tsimerinov, Evgeny I; Scott, Bryan L; Walker, Ashley E; Gurudevan, Swaminatha V; Anene, Francine; Elashoff, Robert M; Thomas, Gail D; Victor, Ronald G

2012-11-28

Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. Like Duchenne muscular dystrophy (DMD), BMD is caused by mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the muscle sarcolemma. Among these is neuronal nitric oxide synthase (nNOSμ), which requires certain spectrin-like repeats in dystrophin's rod domain and the adaptor protein α-syntrophin to be targeted to the sarcolemma. When healthy skeletal muscle is subjected to exercise, sarcolemmal nNOSμ-derived NO attenuates local α-adrenergic vasoconstriction, thereby optimizing perfusion of muscle. We found previously that this protective mechanism is defective-causing functional muscle ischemia-in dystrophin-deficient muscles of the mdx mouse (a model of DMD) and of children with DMD, in whom nNOSμ is mislocalized to the cytosol instead of the sarcolemma. We report that this protective mechanism also is defective in men with BMD in whom the most common dystrophin mutations disrupt sarcolemmal targeting of nNOSμ. In these men, the vasoconstrictor response, measured as a decrease in muscle oxygenation, to reflex sympathetic activation is not appropriately attenuated during exercise of the dystrophic muscles. In a randomized placebo-controlled crossover trial, we show that functional muscle ischemia is alleviated and normal blood flow regulation is fully restored in the muscles of men with BMD by boosting NO-cGMP (guanosine 3',5'-monophosphate) signaling with a single dose of the drug tadalafil, a phosphodiesterase 5A inhibitor. These results further support an essential role for sarcolemmal nNOSμ in the normal modulation of sympathetic vasoconstriction in exercising human skeletal muscle and implicate the NO-cGMP pathway as a putative new target for treating BMD.

Tadalafil alleviates muscle ischemia in patients with Becker muscular dystrophy

PubMed Central

Martin, Elizabeth A.; Barresi, Rita; Byrne, Barry J.; Tsimerinov, Evgeny I.; Scott, Bryan L.; Walker, Ashley E.; Gurudevan, Swaminatha V.; Anene, Francine; Elashoff, Robert M.; Thomas, Gail D.; Victor, Ronald G.

2013-01-01

Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. Like Duchenne muscular dystrophy (DMD), BMD is caused by mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the muscle sarcolemma. Among these is neuronal nitric oxide synthase (nNOSμ), which requires certain spectrin-like repeats in dystrophin’s rod domain and the adaptor protein α-syntrophin to be targeted to the sarcolemma. When healthy skeletal muscle is subjected to exercise, sarcolemmal nNOSμ-derived nitric oxide (NO) attenuates local α-adrenergic vasoconstriction thereby optimizing perfusion of muscle. We found previously that this protective mechanism is defective—causing functional muscle ischemia—in dystrophin-deficient muscles of the mdx mouse (a model of DMD) and of children with DMD, in whom nNOSμ is mislocalized to the cytosol instead of the sarcolemma. Here, we report that this protective mechanism also is defective in men with BMD in whom the most common dystrophin mutations disrupt sarcolemmal targeting of nNOSμ. In these men, the vasoconstrictor response, measured as a decrease in muscle oxygenation, to reflex sympathetic activation is not appropriately attenuated during exercise of the dystrophic muscles. In a randomized placebo-controlled cross-over trial, we show that functional muscle ischemia is alleviated and normal blood flow regulation fully restored in the muscles of men with BMD by boosting NO-cGMP signaling with a single dose of the drug tadalafil, a phosphodiesterase (PDE5A) inhibitor. These results further support an essential role for sarcolemmal nNOSμ in the normal modulation of sympathetic vasoconstriction in exercising human skeletal muscle and implicate the NO-cGMP pathway as a putative new target for treating BMD. PMID:23197572

The influence of amorphization methods on the apparent solubility and dissolution rate of tadalafil.

PubMed

Wlodarski, K; Sawicki, W; Paluch, K J; Tajber, L; Grembecka, M; Hawelek, L; Wojnarowska, Z; Grzybowska, K; Talik, E; Paluch, M

2014-10-01

This study for the first time investigates the solubility and dissolution rate of amorphous tadalafil (Td)--a poorly water soluble chemical compound which is commonly used for treating the erectile dysfunction. To convert the crystalline form of Td drug to its amorphous counterpart we have employed most of the commercially available amorphization techniques i.e. vitrification, cryogenic grinding, ball milling, spray drying, freeze drying and antisolvent precipitation. Among the mentioned methods only quenched cooling of the molten sample was found to be an inappropriate method of Td amorphization. This is due to the thermal decomposition of Td above 200°C, as proved by the thermogravimetric analysis (TGA). Disordered character of all examined samples was confirmed using differential scanning calorimetry (DSC) and X-ray powder diffraction (PXRD). In the case of most amorphous powders, the largest 3-fold increase of apparent solubility was observed after 5 min, indicating their fast recrystallization in water. On the other hand, the partially amorphous precipitate of Td and hypromellose enhanced the solubility of Td approximately 14 times, as compared with a crystalline substance, which remained constant for half an hour. Finally, disk intrinsic dissolution rate (DIDR) of amorphous forms of Td was also examined. Copyright © 2014 Elsevier B.V. All rights reserved.

Impaired Right Ventricular-Pulmonary Arterial Coupling and Effect of Sildenafil in Heart Failure With Preserved Ejection Fraction: An Ancillary Analysis From the Phosphodiesterase-5 Inhibition to Improve Clinical Status And Exercise Capacity in Diastolic Heart Failure (RELAX) Trial.

PubMed

Hussain, Imad; Mohammed, Selma F; Forfia, Paul R; Lewis, Gregory D; Borlaug, Barry A; Gallup, Dianne S; Redfield, Margaret M

2016-04-01

Right ventricular (RV) dysfunction (RVD) is a poor prognostic factor in heart failure with preserved ejection fraction (HFpEF). The physiological perturbations associated with RVD or RV function indexed to load (RV-pulmonary arterial [PA] coupling) in HFpEF have not been defined. HFpEF patients with marked impairment in RV-PA coupling may be uniquely sensitive to sildenafil. In a subset of HFpEF patients enrolled in the Phosphodiesteas-5 Inhibition to Improve Clinical Status And Exercise Capacity in Diastolic Heart Failure (RELAX) trial, physiological variables and therapeutic effect of sildenafil were examined relative to the severity of RVD (tricuspid annular plane systolic excursion [TAPSE]) and according to impairment in RV-PA coupling (TAPSE/pulmonary artery systolic pressure) ratio. The prevalence of atrial fibrillation and diuretic use, n-terminal probrain natriuretic peptide levels, renal dysfunction, neurohumoral activation, myocardial necrosis and fibrosis biomarkers, and the severity of diastolic dysfunction all increased with severity of RVD. Peak oxygen consumption decreased and ventilatory inefficiency (VE/VCO2 slope) increased with increasing severity of RVD. Many but not all physiological derangements were more closely associated with the TAPSE/pulmonary artery systolic pressure ratio. Compared with placebo, at 24 weeks, TAPSE decreased, and peak oxygen consumption and VE/CO2 slope were unchanged with sildenafil. There was no interaction between RV-PA coupling and treatment effect, and sildenafil did not improve TAPSE, peak oxygen consumption, or VE/VCO2 in patients with pulmonary hypertension and RVD. HFpEF patients with RVD and impaired RV-PA coupling have more advanced heart failure. In RELAX patients with RVD and impaired RV-PA coupling, sildenafil did not improve RV function, exercise capacity, or ventilatory efficiency. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00763867. © 2016 American Heart Association, Inc.

Cardioprotective role of tadalafil against cisplatin-induced cardiovascular damage in rats.

PubMed

Saleh, Rasha M; Awadin, Walaa F; El-Shafei, Reham A; Elseady, Yousef Y; Wehaish, Faheim E; Elshal, Mohamed F

2015-10-15

The present study investigated the possible cardioprotective effect of tadalafil (Tad) on cisplatin (CDDP)-induced cardiac and vascular damages in rats. A total number of seventy two healthy male albino rats initially weighting between 200 and 220 g were used and randomly divided into four groups,18 rats in each. The control group received no treatment; CDDP group received a single dose of CDDP (4 mg/kg) intraperitoneal (i.p.) per week for 4 weeks the duration of the experiment; Tad group received 0.4 mg/kg BW Tad i.p. daily and Tad +CDDP group received 0.4 mg/kg BW Tad i.p. +4 mg/kg BW CDDP i.p. The results showed that Tad was able to decrease blood pressure, heart rate, levels of serum cardiac troponin (cTn-I), malondialdehyde (MDA) and increased levels of reduced glutathione (GSH) and nitric oxide (NO) in the heart homogenate sample from CDDP treated rats. Semi-quantitative analysis showed that Tad was able to decrease the histopathological scores of cardiac muscular hyalinzation and fibrosis in three sacrifices in CDDP treated rats. CDDP treated rats showed significantly increased thickening in wall of aorta with an irregular luminal layer of endothelial cell linings in three sacrifices when it was compared to other groups. Moreover, immunohistochemical labeling of α- smooth muscle actin (α-SMA) in aorta revealed significant lower scores in Tad +CDDP group when they were compared to CDDP group. In conclusion, Tad alone did not induce any harmful effects on blood pressure, selective antioxidant, peroxidation markers or cardiac histology, in addition, Tad has a cardio-protective role against CDDP. Copyright © 2015 Elsevier B.V. All rights reserved.

Randomised clinical trial: a leucine-metformin-sildenafil combination (NS-0200) vs placebo in patients with non-alcoholic fatty liver disease.

PubMed

Chalasani, N; Vuppalanchi, R; Rinella, M; Middleton, M S; Siddiqui, M S; Barritt, A S; Kolterman, O; Flores, O; Alonso, C; Iruarrizaga-Lejarreta, M; Gil-Redondo, R; Sirlin, C B; Zemel, M B

2018-06-01

Sirtuin 1 (Sirt1) is suppressed in non-alcoholic fatty liver disease (NAFLD), while its' stimulation or overexpression results in reduced disease severity in pre-clinical NAFLD models. Leucine allosterically activates Sirt1 and synergise with other Sirt/AMPK/NO pathway activators. We developed a triple combination of leucine, metformin and sildenafil (NS-0200), which was effective in a mouse model of non-alcoholic steatohepatitis (NASH). To report the results from a Phase 2, randomised clinical trial of of NS-0200 in 91 subjects with NAFLD (liver fat ≥15% by magnetic resonance imaging-proton-density fat fraction (MRI-PDFF)). Subjects were randomised to placebo, low-dose (1.1 g leucine/0.5 g metformin/0.5 mg sildenafil) or high-dose NS-0200 (1.1 g leucine/0.5 g metformin/1.0 mg sildenafil) b.d. for 16 weeks; change in hepatic fat was assessed via MRI-PDFF, and lipid metabolism was assessed via changes in the lipidomic signature. Seventy subjects completed the trial and met a priori compliance criteria. Analyses were conducted on the full cohort and on those with alanine aminotransferase (ALT) values above median (50 U/L; n = 35). In the full cohort, active treatments did not separate from placebo. High dose NS-0200 reduced hepatic fat by 15.7% (relative change from baseline) in the high ALT group (P < 0.005) while low dose NS-0200 and placebo did not significantly change hepatic fat. Lipidomic analysis showed dose-responsive treatment effects in both overall and high ALT cohorts, with significant decreases in metabolically active lipids and up-regulation of fatty acid oxidation. These data support further evaluation of high-dose NS-0200 for treating NASH, especially in those with elevated ALT (NCT 02546609). © 2018 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

Preparation and characterization of intravaginal vardenafil suppositories targeting a complementary treatment to boost in vitro fertilization process.

PubMed

Gomaa, Eman; Abu Lila, Amr S; Hasan, Azza A; Ghazy, Fakhr-Eldin S

2018-01-01

Vaginal route has been recently considered as a potential route for systemic delivery of drugs with poor oral bioavailability. Vardenafil (VDF) is a relatively new phosphodiesterase-5 inhibitor that exhibits a limited oral bioavailability (≈15%) due to extensive first-pass metabolism. In this study, we attempted to enhance the systemic bioavailability of VDF via its formulation within vaginal suppositories. Witepsol H15 and Suppocire NA50 were adopted as lipophilic suppository bases while polyethylene glycol 4000/400 and glycerogelatin were used as hydrophilic suppository bases. The effect of different base types and/or the incorporation of bioadhesive polymer on in vitro release of VDF were evaluated. The in vivo fate and organ biodistribution of VDF following intravaginal (IVG) administration were also investigated. VDF release from water-soluble bases was higher than that from lipophilic bases. The incorporation of bioadhesive polymers, such as Na alginate, remarkably sustained drug release from suppository base. The organ biodistribution study showed a higher C max (32 times) and AUC 0-4h (20 times) of VDF in uterus following IVG administration of conventional suppositories, compared to oral administration of VDF suspension. In addition, cyclic guanosine monophosphate (cGMP) serum levels, used as an indicator of the in vivo activity of VDF, in animals were higher following IVG administration rather than oral administration. This study suggests that IVG administration of VDF might represent a potential alternative to oral route with superior therapeutic benefits especially when targeting the uterus. Copyright © 2017 Elsevier B.V. All rights reserved.

Analysis of confiscated black market drugs using chromatographic and mass spectrometric approaches.

PubMed

Thevis, Mario; Schrader, Yvonne; Thomas, Andreas; Sigmund, Gerd; Geyer, Hans; Schänzer, Wilhelm

2008-04-01

In the context of house searches in Germany, numerous drugs were confiscated and subjected to chemical analysis, including anabolic agents such as various anabolic-androgenic steroids (stanozolol, testosterone derivatives, trenbolone esters, etc.) and clenbuterol, as well as agents with anti-estrogenic activity (tamoxifen, clomiphene), drugs stimulating virility (sildenafil, tadalafil), and unlabeled plastic bags. Liquid chromatography-tandem mass spectrometry, gas chromatography-mass spectrometry with nitrogen-phosphorus specific detection, gel electrophoresis, and immunological tests were employed to test for the effective content of 70 products. In 18 cases (25.7%), the declared ingredients differed from the actual content, in particular concerning anabolic-androgenic steroids. Nandrolone and trenbolone esters, for instance, were frequently substituted or complemented by various testosterone derivatives, and several testosterone depot formulations originally composed of four different esters were found to contain fewer or wrong components. Except for those drugs supposedly originating from so-called underground labs, fake packings were hardly or not distinguishable from original boxes by visual inspection.

Treatment of erectile dysfunction with sildenafil citrate (Viagra) in parkinsonism due to Parkinson's disease or multiple system atrophy with observations on orthostatic hypotension

PubMed Central

Hussain, I; Brady, C; Swinn, M; Mathias, C; Fowler, C

2001-01-01

OBJECTIVES—To assess the efficacy and safety of sildenafil citrate (Viagra) in men with erectile dysfunction and parkinsonism due either to Parkinson's disease or multiple system atrophy.
METHODS—Twenty four patients with erectile disease were recruited, 12 with Parkinson's disease and 12 with multiple system atrophy, into a randomised, double blind, placebo controlled, crossover study of sildenafil citrate. The starting dose was 50 mg active or placebo medication with the opportunity for dose adjustment depending on efficacy and tolerability. The international index of erectile function questionnaire (IIEF) was used to assess treatment efficacy and a quality of life questionnaire to assess the effect of treatment on sex life and whole life. Criteria for entry included a definite neurological diagnosis and a standing systolic blood pressure of 90-180 mm Hg and diastolic blood pressure of 50-110 mm Hg, on treatment if necessary. Blood pressure was taken at randomisation (visit 2) and crossover (visit 5) lying, sitting, and standing, before and 1 hour after taking the study medication in hospital.
RESULTS—Sidenafil citrate was efficacious in men with parkinsonism with a significant improvement, as demonstrated in questionnaire responses, in ability to achieve and maintain an erection and improvement in quality of sex life. In Parkinson's disease there was minimal change in blood pressure between active and placebo medication. In multiple system atrophy, six patients were studied before recruitment was stopped because three men showed a severe drop in blood pressure 1 hour after taking the active medication. Two were already known to have orthostatic hypotension and were receiving treatment with ephedrine and midodrine but the third had asymptomatic hypotension. However, the blood pressures in all three had been within the inclusion criterion for the study protocol. Despite a significant postural fall in blood pressure after sildenafil, all patients with

Probable neuro sexual mode of action of Casimiroa edulis seed extract versus [correction of verses] sildenafil citrate (Viagra(tm)) on mating behavior in normal male rats.

PubMed

Ali, Syed Tabrez; Rakkah, Nabeeh I

2008-01-01

The present study deals with the aphrodisiac actions of the aqueous extract of the seeds of the hypotensive plant Casimiroa edulis on the sexual behavior of normal male rats. In this investigation 30 healthy male Wister strain white albino rats showing the brisk sexual activity age 15 weeks, weighing 400-450 grams were included. Female rats were artificially brought into estrous by hormonal treatment. Receptivity was checked by exposing them to the male rats and the most receptive females were selected for the stud The mating responses including Mounting Frequency (MF), Intromission Frequency (IF), Mounting Latency (ML), Intromission Latency (IL), Ejaculatory Latency in first and second series (EL1 and EL2) and Post Ejaculatory Interval (PEI) were recorded after treating the animals with 250 mg/kg casimiroa edulis extract (test reference) and 5 mg/kg sildenafil citrate (standard reference) respectively orally per day for 7 days. Both the groups exhibited a significant increase in Mounting Frequency, Intromission Frequency, and first and second ejaculatory latencies, where as Mounting and Intromission latencies and the Post Ejaculatory Interval showed a significant reduction than the controls. Although a similar pattern of mating behavior was observed among the test and the standard groups, however in all the cases as expected, sildenafil produced greater activity than the casimiroa edulis extract. These results suggest the possibility of a similar mode of action of casimiroa edulis and sildenafil citrate on mating behavior in these animals. Our work reported in this research thus provide preliminary evidence that the aqueous seed extract of casimiroa edulis possesses alphrodisiac activity and may be used as an alternative drug therapy to restore sexual functions probably via a neurogenic mode of action.

New drugs of 2003.

PubMed

Hussar, Daniel A

2004-01-01

To provide information regarding the most important properties of the new therapeutic agents marketed in 2003. Product labeling supplemented selectively with published studies and drug information reference sources. By the author. By the author. The 28 new therapeutic agents marketed in the United States during 2003 are reviewed in this article: adalimumab, agalsidase beta, alefacept, alfuzosin hydrochloride, aprepitant, atazanavir sulfate, atomoxetine hydrochloride, bortezomib, daptomycin, efalizumab, eletriptan hydrobromide, emtricitabine, enfuvirtide, eplerenone, gefitinib, icodextrin, laronidase, memantine hydrochloride, mequinol/tretinoin, miglustat, nitazoxanide, omalizumab, palonosetron hydrochloride, pegvisomant, rosuvastatin calcium, tadalafil, tositumomab and iodine I 131 tositumomab, and vardenafil hydrochloride. Indications and information on dosage and administration for these agents are reviewed, as are the most important pharmacokinetic properties, adverse events, drug interactions, and other precautions. Practical considerations for the use of the new agents are also discussed. When possible, the properties of the new drugs are compared with those of older drugs marketed for the same indications. A number of the new therapeutic agents marketed in 2003 have important advantages over older medications. An understanding of the properties of these agents is important for the pharmacist to effectively counsel patients about their use and to serve as a valuable source of information for other health professionals regarding these drugs.

Design and physicochemical stability studies of paediatric oral formulations of sildenafil.

PubMed

Provenza, N; Calpena, A C; Mallandrich, M; Halbaut, L; Clares, B

2014-01-02

Personalized medicine is a challenging research area in paediatric treatments. Elaborating new paediatric formulations when no commercial forms are available is a common practice in pharmacy laboratories; among these, oral liquid formulations are the most common. But due to the lack of specialized equipment, frequently studies to assure the efficiency and safety of the final medicine cannot be carried out. Thus the purpose of this work was the development, characterization and stability evaluation of two oral formulations of sildenafil for the treatment of neonatal persistent pulmonary hypertension. After the establishment of a standard operating procedure (SOP) and elaboration, the physicochemical stability parameters appearance, pH, particle size, rheological behaviour and drug content of formulations were evaluated at three different temperatures for 90 days. Equally, prediction of long term stability, as well as, microbiological stability was performed. Formulations resulted in a suspension and a solution slightly coloured exhibiting fruity odour. Formulation I (suspension) exhibited the best physicochemical properties including Newtonian behaviour and uniformity of API content above 90% to assure an exact dosification process. Copyright © 2013 Elsevier B.V. All rights reserved.

Prevention of valproic acid-induced neural tube defects by sildenafil citrate.

PubMed

Tiboni, Gian Mario; Ponzano, Adalisa

2015-08-15

This study was undertaken to test the effects of sildenafil citrate (SC), a type 5 phosphodiesterase inhibitor, on valproic acid (VPA)-induced teratogenesis. On gestation day (GD) 8, ICR (CD-1) mice were treated by gastric intubation with SC at 0 (vehicle), 1.0, 2.5, 5.0 or 10mg/kg. One hour later, animals received a teratogenic dose of VPA (600mg/kg) or vehicle. Developmental endpoints were evaluated near the end of gestation. Twenty-eighth percent of fetuses exposed to VPA had neural tube defects (exencephaly). Pretreatment with SC at 2.5, 5.0 or 10mg/kg significantly reduced the rate of VPA-induced exencephaly to 15.9%, 13.7%, and 10.0%, respectively. Axial skeletal defects were observed in 75.8% of VPA-exposed fetuses. Pre-treatment with SC at 10mg/kg, but not at lower doses, significantly decreased the rate of skeletally affected fetuses to 61.6%. These results show that SC, which prolongs nitric oxide (NO) signaling action protects from VPA-induced teratogenesis. Copyright © 2015 Elsevier Inc. All rights reserved.

Effect of chronic low-dose tadalafil on penile cavernous tissues in diabetic rats.

PubMed

Mostafa, Mohamed E; Senbel, Amira M; Mostafa, Taymour

2013-06-01

To assess the effect of chronic low-dose administration of tadalafil (Td) on penile cavernous tissue in induced diabetic rats. The study investigaged 48 adult male albino rats, comprising a control group, sham controls, streptozotocin-induced diabetic rats, and induced diabetic rats that received Td low-dose daily (0.09 mg/200 g weight) for 2 months. The rats were euthanized 1 day after the last dose. Cavernous tissues were subjected to histologic, immunohistochemical, morphometric studies, and measurement of intracavernosal pressure and mean arterial pressure in anesthetized rats. Diabetic rats demonstrated dilated cavernous spaces, smooth muscles with heterochromatic nuclei, degenerated mitochondria, vacuolated cytoplasm, and negative smooth muscle immunoreactivity. Nerve fibers demonstrated a thick myelin sheath and intra-axonal edema, where blood capillaries exhibited thick basement membrane. Diabetic rats on Td showed improved cavernous organization with significant morphometric increases in the area percentage of smooth muscles and elastic tissue and a significant decrease of fibrous tissue. The Td-treated group showed enhanced erectile function (intracavernosal pressure/mean arterial pressure) at 0.3, 0.5, 1, 3, and 5 Hz compared with diabetic group values at the respective frequencies (P <.05) that approached control values. Chronic low-dose administration of Td in diabetic rats is associated with substantial improvement of the structure of penile cavernous tissue, with increased smooth muscles and elastic tissue, decreased fibrous tissue, and functional enhancement of the erectile function. This raises the idea that the change in penile architecture with Td treatment improves erectile function beyond its half-life and its direct pharmacologic action on phosphodiesterase type 5. Copyright © 2013 Elsevier Inc. All rights reserved.

High-Energy Ball Milling as Green Process To Vitrify Tadalafil and Improve Bioavailability.

PubMed

Krupa, Anna; Descamps, Marc; Willart, Jean-François; Strach, Beata; Wyska, Elżbieta; Jachowicz, Renata; Danède, Florence

2016-11-07

In this study, the suitability of high-energy ball milling was investigated with the aim to vitrify tadalafil (TD) and improve its bioavailability. To achieve this goal, pure TD as well as binary mixtures composed of the drug and Soluplus (SL) were coprocessed by high-energy ball milling. Modulated differential scanning calorimetry (MDSC) and X-ray powder diffraction (XRD) demonstrated that after such coprocessing, the crystalline form of TD was transformed into an amorphous form. The presence of a single glass transition (T g ) for all the comilled formulations indicated that TD was dispersed into SL at the molecular level, forming amorphous molecular alloys, regardless of the drug concentration. The high values of T g determined for amorphous formulations, ranging from 70 to 147 °C, foreshow their high stability during storage at room temperature, which was verified by XRD and MDSC studies. The stabilizing effect of SL on the amorphous form of TD in comilled formulations was confirmed. Dissolution tests showed immediate drug release with sustained supersaturation in either simulated gastric fluid of pH 1.2 or in phosphate buffer of pH 7.2. The beneficial effect of both amorphization and coamorphization on the bioavailability of TD was found. In comparison to aqueous suspension, the relative bioavailability of TD was only 11% for its crystalline form and 53% for the crystalline physical mixture, whereas the bioavailability of milled amorphous TD and the comilled solid dispersion was 128% and 289%, respectively. Thus, the results provide evidence that not only the presence of polymeric surfactant but also the vitrification of TD is necessary to improve bioavailability.

Ocular safety of Viagra, (sildenafil citrate).

PubMed Central

Laties, A M; Fraunfelder, F T

1999-01-01

To date, sildenafil citrate (Viagra) gives every evidence of being a safe drug for the eye despite a series of expressed concerns. A review of how its ocular safety profile has been identified offers insights into the strengths and weaknesses of present systems and resources for judging the ocular safety of Viagra or, for that matter, of any new drug. Such insights include: The great value of careful, informed assessment of preclinical information gleaned from laboratory experiments. By and large, such assessments point the way toward appropriate clinical evaluation. For Viagra, early in its development it was noted that besides exerting a major inhibitory effect on the intended target, the vascular-associated enzyme phosphodiesterase 5 (PDE5), the drug also exerts a lesser but definite inhibitory effect on the closely related PDE6, located in the retina. For this reason, preclinical evaluation of the drug included electroretinography plus postmortem histology. In addition, an extended eye examination was incorporated into clinical protocols. The often chaotic but invaluable information stream that becomes available once marketing approval has been gained and large populations begin to use a drug. False alarms, misattribution, and erroneous information are the order of the day. Nevertheless, as information accumulates, patterns of response clarify and the true nature of special susceptibility for subpopulations, if any, becomes apparent. A role for the astute clinician remains: Subtle changes or unusual risks for subpopulations can be missed entirely for long periods of time. A manifest need for improvement in evaluation of postmarketing side-effects. This need has led to the establishment of a new discipline: pharmacoepidemiology. In ophthalmology, the National Registry of Drug Induced Ocular Side-Effects maintains a constant and invaluable surveillance. Examples are supplied to illustrate each of these major points: Our presentation will include data gleaned from

Mitigation of indomethacin-induced gastric mucosal lesions by a potent specific type V phosphodiesterase inhibitor